transforming-growth-factor-beta and Coronary-Artery-Disease

Coronary artery disease (CAD) is one of the leading causes of mortality globally and has long been known to be heritable; however, the specific genetic factors involved have yet to be identified. Recent advances have started to unravel the genetic architecture of this disease and set high expectations about the future use of novel susceptibility variants for its prevention, diagnosis, and treatment. In the past decade, there has been major progress in this area. New tools, like common variant association studies, genome-wide association studies, meta-analyses, and genetic risk scores, allow a better understanding of the genetic risk factors driving CAD. In recent years, researchers have conducted further studies that confirmed the role of numerous genetic factors in the development of CAD. These include genes that affect lipid and carbohydrate metabolism, regulate the function of the endothelium and vascular smooth muscles, influence the coagulation system, or affect the immune system. Many CAD-associated single-nucleotide polymorphisms have been identified, although many of their functions are largely unknown. The inflammatory process that occurs in the coronary vessels is very important in the development of CAD. One important mediator of inflammation is TGFβ1. TGFβ1 plays an important role in the processes leading to CAD, such as by stimulating macrophage and fibroblast chemotaxis, as well as increasing extracellular matrix synthesis. This review discusses the genetic risk factors related to the development of CAD, with a particular focus on polymorphisms of the transforming growth factor β (TGFβ) gene and its receptor.

Topics: Coronary Artery Disease; Genome-Wide Association Study; Humans; Polymorphism, Single Nucleotide; Risk Factors; Transforming Growth Factor beta

Excessive vascular smooth muscle cell (SMC) proliferation, migration and extracellular matrix (ECM) synthesis are key events in the development of intimal hyperplasia, a pathophysiological response to acute or chronic sources of vascular damage that can lead to occlusive narrowing of the vessel lumen. Atherosclerosis, the primary cause of coronary artery disease, is characterised by chronic vascular inflammation and dyslipidemia, while revascularisation surgeries such as coronary stenting and bypass grafting represent acute forms of vascular injury. Gene knockouts of transforming growth factor-beta (TGFβ), its receptors and downstream signalling proteins have demonstrated the importance of this pleiotropic cytokine during vasculogenesis and in the maintenance of vascular homeostasis. Dysregulated TGFβ signalling is a hallmark of many vascular diseases, and has been associated with the induction of pathological vascular cell phenotypes, fibrosis and ECM remodelling. Here we present an overview of TGFβ signalling in SMCs, highlighting the ways in which this multifaceted cytokine regulates SMC behaviour and phenotype in cardiovascular diseases driven by intimal hyperplasia.

Topics: Animals; Cell Movement; Cell Proliferation; Coronary Artery Disease; Humans; Myocytes, Smooth Muscle; Signal Transduction; Transforming Growth Factor beta

To investigate the association between common transforming growth factor beta (TGF-β) single nucleotide polymorphisms (SNP) and significant complications of coronary heart disease (CHD).. We performed a meta-analysis of published case-control studies assessing the association of TGF-β SNPs with a range of CHD complications. A random effects model was used to calculate odds ratios and confidence intervals. Analyses were conducted for additive, dominant and recessive modes of inheritance.. Six studies involving 5535 cases and 2970 controls examining the association of common SNPs in TGF-β1 with CHD were identified. Applying a dominant model of inheritance, three TGF-β1 SNPs were significantly associated with CHD complications: The T alleles of rs1800469 (OR = 1.125, 95% CI 1.016-1.247, p = 0.031) and rs1800470 (OR = 1.146, 95% CI 1.026-1.279, p = 0.021); and the C allele of rs1800471 (OR = 1.207, 95% CI 1.037-1.406, p = 0.021).. This meta-analysis suggests that common genetic polymorphisms in TGF-β1 are associated with complications of CHD.

Topics: Case-Control Studies; Coronary Artery Disease; Genetic Predisposition to Disease; Genotype; Humans; Models, Genetic; Polymorphism, Single Nucleotide; Transforming Growth Factor beta; Transforming Growth Factor beta1

The extracellular matrix is no longer seen as the static embedding in which cells reside; it has been shown to be involved in cell proliferation, migration and cell-cell interactions. Turnover of the different extracellular matrix components is an active process with multiple levels of regulation. Collagen, a major extracellular matrix constituent of the myocardium and the arterial vascular wall, is synthesized by (myo)fibroblasts in the myocardium and smooth muscle cells in the medial arterial vascular wall. Its degradation is controlled by proteinases, which include matrix metalloproteinases. This review will focus on the impact of fibrosis and especially collagen turnover on the progression of heart failure and atherosclerosis, two of the main cardiovascular pathologies. We will discuss data from human studies and animal models, with an emphasis on the effects of interventions on collagen synthesis and degradation. We conclude that there is a dynamic (dis)balance in the rate of collagen synthesis and degradation during heart failure and atherosclerosis, which makes the outcome of interventions not always predictable. Alternative approaches for intervening in collagen metabolism will be discussed as possible therapeutic intervention strategies.

Topics: Animals; Animals, Genetically Modified; Collagen; Coronary Artery Disease; Coronary Vessels; Extracellular Matrix; Heart Failure; Humans; Hypolipidemic Agents; Matrix Metalloproteinases; Mice; Models, Animal; Muscle, Smooth, Vascular; Myocardium; Randomized Controlled Trials as Topic; Receptors, LDL; Transforming Growth Factor beta

Cholesterol is known to participate in atheromatous plaque formation coming from blood stream and affecting vascular endothelium in environment of elevated low-density lipoproteins (LDL). Nevertheless, the occurrence of single atheromatous plaque evidences the possibility of local lipoprotein accumulation by vascular wall without systemic increase in serum LDLs. The author hypothesizes that in the absence of hypercholesterolemia atheroma can evolve through the utilization of modified LDL and free or etherified cholesterol, that remain in media non-removed by high density lipoproteins (HDL) owing to their structural damage after local vascular wall ischemia caused by vasa vasorum disorders. Disturbances in HDL acceptor function and transport of cholesterol and modified LDL to blood circulation and further into liver are followed by local accumulation of these products in smooth muscle cells. Overloaded by lipids smooth muscle cells move through internal fenestrated membrane thus activating receptor mechanism for transmission of modified lipoproteins to monocytes and capture of endothelial membrane and amorphous lipids by them in local lipid peroxidation area. A framework for hypothesis experimental and clinical testing is suggested.

Topics: Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Humans; Hypercholesterolemia; Insulin-Like Growth Factor I; Lipid Peroxidation; Muscle, Smooth; Platelet-Derived Growth Factor; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vasa Vasorum

Smooth muscle cells migrate into the vascular intima, proliferate, and lay down extracellular matrix, thereby forming an important component of the occlusive mass of atherosclerotic plaques in native arteries and in saphenous vein grafts. The viability of smooth muscle cells and the integrity of their surrounding extracellular matrix also determine the liability of plaques to rupture and hence precipitate myocardial infarction and vein graft occlusion. This update reviews recent developments in the molecular understanding of relevant aspects of smooth muscle cell biology. It highlights the increasing importance attached to interactions between growth factors and components of the extracellular matrix in regulating migration and proliferation and the new roles assigned to apoptosis in these cells. It illustrates, furthermore, how the application of the techniques of molecular biology is identifying new targets for conventional and gene therapy.

Topics: Animals; Apoptosis; Cell Division; Cell Movement; Coronary Artery Disease; Extracellular Matrix; Humans; Metalloendopeptidases; Muscle, Smooth, Vascular; Platelet-Derived Growth Factor; Saphenous Vein; Transforming Growth Factor beta

Very little is known about the development of postatherectomy or postangioplasty restenosis. Morphologically, restenosis lesions are primarily composed of smooth muscle cells with associated matrix proteins and develop within 3-6 months. Although some degree of smooth muscle cell proliferation is a necessary part of the healing process after injury, it is unclear why only some individuals develop clinically significant lesions. Platelet deposition and release of growth factors have been postulated to be important in initiating the cellular growth response after vascular injury. Current data suggest that growth factors synthesized locally in the vessel wall may be very important in controlling smooth muscle proliferation. In addition, atherosclerotic plaques contain many procoagulant proteins that are exposed by angioplasty or atherectomy. These proteins stimulate a coagulation response and the activation of thrombin, resulting in platelet aggregation and thrombus formation. Thrombin mediates several biologic responses that may facilitate vascular lesion formation and can act directly as a smooth muscle mitogen. Vascular lesion formation as a result of percutaneous transluminal coronary angioplasty or atherectomy may be stimulated by a combination of factors, including platelet deposition and thrombin action, ultimately generating an autocrine growth response in the vessel wall.

Topics: Angioplasty, Balloon, Coronary; Animals; Atherectomy, Coronary; Constriction, Pathologic; Coronary Artery Disease; Coronary Vessels; Fibroblast Growth Factor 2; Humans; Muscle, Smooth, Vascular; Papio; Platelet-Derived Growth Factor; Recurrence; Thrombin; Transforming Growth Factor beta

Nowadays there is a strong necessity in identifying patients who may be exposed to the risk for future cardiovascular events like progressive atherosclerotic disease. Biomarkers are valuable tools for this purpose. Coronary artery calcification (CAC) is utilized as an important tool for the global risk assessment of cardiovascular events in individuals with intermediate risk. Decorin (DCN) is a small leucine-rich proteoglycan that induces calcification of arterial smooth muscle cell and localizes to mineral deposition in human atherosclerotic plaque. The main purpose of this clinical study was to find out the correlation between Decorin serum concentration and CAC in human for the first time.. In this study 84 patients with coronary artery disease who fulfilled inclusion and exclusion criteria, entered the study. For all patients a questionnaire consisting demographic data and traditional cardiovascular risk factors were completed. CT-Angiography was carried out to determine coronary artery calcium score and ELISA method was used for measuring DCN serum concentrations.. No significant correlation between DCN serum concentration and total CAC score and also CAC of left anterior descending, right coronary artery, left main coronary artery and circumflex was found in the study population (P>0.05).. On the basis of our results DCN serum concentration is not a suitable biomarker of coronary artery disease. However, more studies with higher sample size are necessary for its confirmation.

Topics: Aged; Biomarkers; Calcinosis; Comorbidity; Computed Tomography Angiography; Coronary Artery Disease; Decorin; Female; Humans; Lipids; Male; Middle Aged; Myocardial Ischemia; Pilot Projects; Risk Factors; Surveys and Questionnaires; Transforming Growth Factor beta

Use of HMG-CoA reductase inhibitors (statins) and angiotensin II type 1 (AT(1)) receptor antagonists reduces the incidence of cardiovascular events. The cytokines macrophage colony-stimulating factor (M-CSF) and transforming growth factor (TGF)-beta may exert proatherogenic and antiatherogenic effects, respectively. In this study, we examined whether treatment with a statin or an AT(1) receptor antagonist alters M-CSF and TGF-beta levels in patients with coronary artery disease.. Twenty-seven consecutive patients with coronary artery disease were randomly assigned to the following three treatment groups for 8 weeks: simvastatin 5 mg/day (n = 10); losartan 50 mg/day (n = 9); or control (usual treatment; n = 8). Blood samples were collected before and after treatment.. Clinical characteristics and baseline cytokine levels were comparable among the three groups. Serum levels of M-CSF were significantly decreased only in the simvastatin group (from 403 +/- 71 to 303 +/- 116 pg/mL; p = 0.009). Plasma levels of TGF-beta were significantly increased only in the losartan group (from 5.01 +/- 1.13 to 7.50 +/- 3.83 ng/mL; p = 0.021). Simvastatin decreased serum M-CSF levels independently of changes in total cholesterol or low-density lipoprotein-cholesterol.. The results of this study indicate that simvastatin decreases serum levels of M-CSF while losartan increases plasma levels of TGF-beta, suggesting that the two drugs may have different anti-atherosclerotic properties.

Topics: Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Biomarkers; Blood Pressure; C-Reactive Protein; Cholesterol, LDL; Coronary Artery Disease; Cytokines; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Losartan; Macrophage Colony-Stimulating Factor; Male; Middle Aged; Simvastatin; Transforming Growth Factor beta; Treatment Outcome

The objective was to evaluate the effect of hormone replacement therapy (HRT) on plasma homocysteine levels in postmenopausal women with coronary artery disease (CAD) and to investigate associations of homocysteine to other cardiovascular risk factors.. The women in this single-center, controlled, and randomized study were examined at baseline, and after 3 and 12 months, after they had been recruited consecutively from patients referred for investigational coronary angiography. All analyses were performed examiner blind. They were randomized to HRT consisting of transdermal application of continuous 17beta-estradiol with cyclic medroxyprogesterone acetate (MPA) tablets for 14 days every 3rd month, or to a control group.. After 3 months of unopposed 17beta-estradiol, no significant effect on homocysteine was observed compared to the control group. The absolute decrease of 5% in median plasma homocysteine levels after 12-month HRT did not reach statistical significance. Plasma homocysteine seemed slightly higher in women with three- or four-vessel disease, but the difference was not significant. With increasing homocysteine levels, free tissue factor pathway inhibitor (TFPI) antigen increased, whereas E-selectin decreased. In women with diabetes or elevated blood glucose >6.0 mmol/l, plasma homocysteine was correlated to body mass index, C-peptide and insulin as well as age.. Transdermal application of 17beta-estradiol and sequential MPA do not affect plasma homocysteine in women with established CAD. Plasma homocysteine is stable in women with CAD over time, and unless special intervention is undertaken, repetitive measurements are not necessary in this particular group of high-risk individuals. The circulating anticoagulant TEPI is related to plasma homocysteine.

Topics: Administration, Cutaneous; Age Factors; Aged; Biomarkers; Body Mass Index; C-Peptide; Coronary Artery Disease; E-Selectin; Estradiol; Estrogen Replacement Therapy; Female; Homocysteine; Humans; Intercellular Adhesion Molecule-1; Lipoprotein(a); Medroxyprogesterone Acetate; Middle Aged; Postmenopause; Progesterone Congeners; Severity of Illness Index; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Treatment Outcome; Vascular Cell Adhesion Molecule-1; Women's Health

Atherosclerotic plaque is considered the hallmark of atherosclerotic lesions in coronary atherosclerosis (CAS), the primary pathogenesis in coronary artery disease (CAD), which develops and progresses through a complex interplay between immune cells, vascular cells, and endothelial shear stresses. Early diagnosis of CAS is critical for avoiding plaque rupture and sudden death. Therefore, identifying new CAD biomarkers linked to vessel wall functions, such as RNA molecules with their distinct signature, is a promising development for these patients. With this rationale, the present study investigated the expression level of the vascular-related RNA transcripts (lncRNA ANRIL, miRNA-126-5p, CDK4, CDK6, TGF-β, E-cadherin, and TNF-α) implicated in the cellular vascular function, proliferation, and inflammatory processes.. A case-control study design with a total of 180 subjects classified participants into two groups; CAD and control groups. The relative expression levels of the seven transcripts under study-selected using online bioinformatics tools and current literature-were assessed in the plasma of all study participants using RT-qPCR. Their predictive significance testing, scoring of disease prioritization, enrichment analysis, and the miRNA-mRNA regulatory network was investigated.. The relative expression levels of all seven of the circulating vascular-related transcripts under study were statistically significant between CAD patients and controls. Receiver operating characteristic (ROC) analysis results indicated the statistical significance of all the transcripts under study with CDK4 showing the highest area under the curve (AUC) equivalent to 0.91, followed by E-cadherin (0.90), miRNA-126-5p (0.83), ANRIL (0.82), TNF-α (0.63), TGF-β (0.62), and CDK6 (0.59), in descending order. A strong association was detected between most of the transcripts studied in CAD patients with a significant Spearman's correlation coefficient with a two-tailed significance of p < 0.001. Network analysis revealed a strong relationship between the five circulating vasculature transcripts studied and their target miRNAs and miR-126-5p, but not for ANRIL.. The seven circulating vascular-related RNA transcripts under study could serve as potential CAD biomarkers, reflecting the cellular vascular function, proliferation, and inflammatory processes in CAD patients. Therefore, blood transcriptome analysis opens new frontiers for the non-invasive diagnosis of CAD.

Topics: Biomarkers; Case-Control Studies; Coronary Artery Disease; Humans; MicroRNAs; Plaque, Atherosclerotic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Vascular smooth muscle cells (SMCs) plasticity is a central mechanism in cardiovascular health and disease. We aimed at providing cellular phenotyping, epigenomic and proteomic depiction of SMCs derived from induced pluripotent stem cells and evaluating their potential as cellular models in the context of complex diseases.. Human induced pluripotent stem cell lines were differentiated using RepSox (R-SMCs) or PDGF-BB (platelet-derived growth factor-BB) and TGF-β (transforming growth factor beta; TP-SMCs), during a 24-day long protocol. RNA-Seq and assay for transposase accessible chromatin-Seq were performed at 6 time points of differentiation, and mass spectrometry was used to quantify proteins.. Both induced pluripotent stem cell differentiation protocols generated SMCs with positive expression of SMC markers. TP-SMCs exhibited greater proliferation capacity, migration and lower calcium release in response to contractile stimuli, compared with R-SMCs. Genes involved in the contractile function of arteries were highly expressed in R-SMCs compared with TP-SMCs or primary SMCs. R-SMCs and coronary artery transcriptomic profiles were highly similar, characterized by high expression of genes involved in blood pressure regulation and coronary artery disease. We identified. Both induced pluripotent stem cell-derived SMCs models present complementary cellular phenotypes of high relevance to SMC plasticity. These cellular models present high potential to study functional regulation at genetic risk loci of main arterial diseases.

Topics: Becaplermin; Cell Differentiation; Cells, Cultured; Chromatin; Coronary Artery Disease; Humans; Induced Pluripotent Stem Cells; Myocytes, Smooth Muscle; Proteomics; Transcriptome; Transforming Growth Factor beta

Extracorporeal shockwave myocardial revascularization (ESMR) is a therapy for refractory angina pectoris. Our aim was to assess the efficacy and safety of ESMR in the management of patients with stable coronary artery disease (CAD) and heart failure as well as its effects on inflammation and angiogenesis. In this single-arm prospective trial, we included 48 patients with CAD, myocardial ischemia assessed by radionuclide imaging, echocardiographic evidence of left ventricular systolic dysfunction and without revascularization options. Changes in angina grading score, myocardial perfusion, left ventricular ejection fraction, and six-minute walk test after ESMR therapy were used for efficacy assessment. Changes of inflammation and angiogenesis biomarkers were also evaluated. ESMR therapy was performed using a commercially available cardiac shockwave generator system (Cardiospec; Medispec). After 9 weeks of ESMR therapy, a significant improvement was found regarding the initial angina class, severity of ischemia, left ventricular ejection fraction, and six-minute walk test in most patients. No deleterious side effects after treatment were detected. Regarding biomarkers, endothelial progenitor cells and angiopoietin-3 were significantly increased whereas IL-18 and TGF-β were significantly decreased after ESMR in the total group. Notably, VEGF, IL-1ß, and lipoxin A4 levels were significantly increased only in patients with myocardial ischemia improvement. In conclusion, ESMR therapy is safe and effective in most but not all patients with CAD and heart failure. ESMR is associated with increased markers of angiogenesis and decreased markers of inflammation. Myocardial ischemia improvement after ESMR is associated with increased markers of angiogenesis and pro-resolving mediators.

Topics: Aged; Angina Pectoris; Angiopoietin-Like Protein 1; Angiopoietin-like Proteins; Coronary Artery Disease; Cytokines; Endothelial Progenitor Cells; Extracorporeal Shockwave Therapy; Female; Heart Failure; Humans; Interleukin-18; Interleukin-1beta; Lipoxins; Male; Middle Aged; Myocardial Perfusion Imaging; Myocardial Revascularization; Prospective Studies; Severity of Illness Index; Stroke Volume; Transforming Growth Factor beta; Treatment Outcome; Vascular Endothelial Growth Factor A; Ventricular Dysfunction, Left; Walk Test

Topics: Animals; Anticholesteremic Agents; Aorta; Carotid Artery Diseases; Coronary Artery Disease; Interleukin-10; Interleukin-1beta; Interleukin-6; Lipids; Plaque, Atherosclerotic; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-1; Simvastatin; Smad Proteins; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta

Nowadays we are surrounded by a plethora of bioinformatics tools, powerful enough to deal with the large amounts of data arising from proteomic studies, but whose application is sometimes hard to find. Therefore, we used a specific clinical problem - to discriminate pathophysiology and potential biomarkers between two similar cardiovascular diseases, aortic valve stenosis (AVS) and coronary artery disease (CAD) - to make a step-by-step guide through four bioinformatics tools: STRING, DisGeNET, Cytoscape and ClueGO. Proteome data was collected from articles available on PubMed centered on proteomic studies enrolling subjects with AVS or CAD. Through the analysis of gene ontology provided by STRING and ClueGO we could find specific biological phenomena associated with AVS, such as down-regulation of elastic fiber assembly, and with CAD, such as up-regulation of plasminogen activation. Moreover, through Cytoscape and DisGeNET we could pinpoint surrogate markers either for AVS (e.g. popeye domain containing protein 2 and 28S ribosomal protein S36, mitochondrial) or for CAD (e.g. ankyrin repeat and SOCS box protein 7) which deserve future validation. Data recycling and integration as well as research orientation are among the main advantages of resorting to bioinformatics analysis, hence these tutorials can be of great convenience for proteomics investigators.. As we saw for aortic valve stenosis and coronary artery disease, it can be of great relevance to perform preliminary bioinformatics analysis with already published proteomics data. It not only saves us time in the lab (avoiding work duplication) as it points out new hypothesis to explain the phenotypical presentation of the diseases as well as new surrogate markers with clinical relevance, deserving future scrutiny. These essential steps can be easily overcome if one follows the steps proposed in our tutorial for STRING, DisGeNET, Cytoscape and ClueGO utilization.

Topics: Aortic Valve Stenosis; Computational Biology; Coronary Artery Disease; Databases, Protein; Gene Ontology; Glutathione Transferase; Humans; Proteome; Transforming Growth Factor beta

Cytokines, which typically regulate the immune responses, play a role in cardiovascular diseases such as coronary artery diseases (CAD) and ischemic heart diseases (IHD). The aims of this study were to evaluate serum levels of IL-6, IL-8, TGF-β and TNF-α in patients with or without CAD, as well as stable angina, and to assess the effects of drug administration on the serum levels of these cytokines. Serum levels of the cytokines were analyzed in the three groups: patients with acute coronary syndrome, stable angina and participants with normal coronary arteries as controls. Cohort study of the patients showed that Nitrocontin was the only drug used in a significantly different pattern between the groups where it was used less frequently in patients with stable angina compared to the acute coronary syndrome or control groups. Serum levels of the evaluated cytokines were not different neither between the studied groups nor between the groups with variable Gensini scores. However, IL-8 in controls that were not engaged in regular exercise was higher than the controls performing regular exercise. In the stable angina group, TNF-α in non-smokers was higher than the smokers. It was revealed that serum levels of pro-inflammatory cytokines are not associated with atherosclerosis and stable angina in patients from the South-East of Iran. However, suppressed expression of TGF-β, may increase the risk of CAD. Exercise can reduce the risk of CAD through downregulation of pro-inflammatory cytokines.

Topics: Angina, Stable; Case-Control Studies; Coronary Artery Disease; Coronary Vessels; Cross-Sectional Studies; Exercise; Female; Gene Expression; Humans; Interleukin-6; Interleukin-8; Iran; Male; Middle Aged; Nitroglycerin; Risk Factors; Smoking; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vasodilator Agents

Although numerous genetic loci have been associated with coronary artery disease (CAD) with genome wide association studies, efforts are needed to identify the causal genes in these loci and link them into fundamental signaling pathways. Recent studies have investigated the disease mechanism of CAD associated gene SMAD3, a central transcription factor (TF) in the TGFβ pathway, investigating its role in smooth muscle biology. In vitro studies in human coronary artery smooth muscle cells (HCASMC) revealed that SMAD3 modulates cellular phenotype, promoting expression of differentiation marker genes while inhibiting proliferation. RNA sequencing and chromatin immunoprecipitation sequencing studies in HCASMC identified downstream genes that reside in pathways which mediate vascular development and atherosclerosis processes in this cell type. HCASMC phenotype, and gene expression patterns promoted by SMAD3 were noted to have opposing direction of effect compared to another CAD associated TF, TCF21. At sites of SMAD3 and TCF21 colocalization on DNA, SMAD3 binding was inversely correlated with TCF21 binding, due in part to TCF21 locally blocking chromatin accessibility at the SMAD3 binding site. Further, TCF21 was able to directly inhibit SMAD3 activation of gene expression in transfection reporter gene studies. In contrast to TCF21 which is protective toward CAD, SMAD3 expression in HCASMC was shown to be directly correlated with disease risk. We propose that the pro-differentiation action of SMAD3 inhibits dedifferentiation that is required for HCASMC to expand and stabilize disease plaque as they respond to vascular stresses, counteracting the protective dedifferentiating activity of TCF21 and promoting disease risk.

Topics: Basic Helix-Loop-Helix Transcription Factors; Binding Sites; Cell Differentiation; Coronary Artery Disease; Epistasis, Genetic; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Muscle, Smooth, Vascular; Polymorphism, Single Nucleotide; Primary Cell Culture; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

Collagen deposition is a hallmark of atherosclerosis. Although compromised collagen I degradation has been implied in the pathogenesis of atherosclerosis, the molecular mechanisms are still unclear. Thus, we determined the role of CD38, an enzyme involved in cellular calcium modulation and autophagic flux, in the regulation of collagen I degradation in coronary arterial myocytes (CAMs).In primary cultured CAMs from CD38

Topics: ADP-ribosyl Cyclase 1; Animals; Autophagy; Cells, Cultured; Collagen Type I; Coronary Artery Disease; Coronary Vessels; Diet, Western; Lysosomes; Male; Matrix Metalloproteinase 9; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; Phagosomes; Proteasome Inhibitors; Proteolysis; RNA, Messenger; Signal Transduction; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta

Kawasaki disease (KD) is a systemic vasculitis childhood disease frequently complicating coronary artery lesions (CALs). Recently, the gene encoding a disintegrin and metalloprotease 17 (ADAM17) was found to modify vascular pathology in humans by differentially regulating the transforming growth factor-β (TGF-β) signaling pathway, which affects KD/CAL susceptibility. To explore the potential role of ADAM17 in KD occurrence and outcomes, we investigated the association of 28 single nucleotide polymorphisms (SNPs) in ADAM17 and three pathway genes of TGF-β signaling with KD phenotypes in a Han Chinese population, including 392 KD patients and 421 non-KD controls. Three ADAM17 SNPs showed an association with KD risk, which was further confirmed by haplotype analysis. The effect of ADAM17 on KD was also shown by multi-variable logistic regression analysis. In two-locus model analyses with SNPs in ADAM17 and TGF-β signaling pathway genes, stronger compound effects on the risk of KD and secondary CAL formation were observed relative to comparable single SNPs.. Our results suggest that ADAM17 contributes to the KD risk and is involved in secondary CAL formation via the TGF-β/SMAD3 signaling pathway. This further enriches our understanding of the importance of the signaling pathway in KD occurrence and outcomes.. • The transforming growth factor (TGF)-β/SMAD3 signaling pathway greatly influences susceptibility to Kawasaki disease (KD) and secondary coronary artery lesions (CALs) and/or the treatment response of intravenous immunoglobulin. • A disintegrin and metalloprotease 17 (ADAM17) effectively reduces TGF-β signaling by cleaving TGF-β receptor type-1, while ADAM17 genetic variants modify human vascular pathology by differentially regulating this signaling although it is unknown whether ADAM17 contributes to KD phenotypes. What is New: • ADAM17 genetic variants were shown to be associated with KD risk, even when excluding the influence of TGF-β signaling pathway genes, suggesting that ADAM17 is an important KD susceptibility-related genetic locus. • The more significant compound effects of two-locus models, combining single nucleotide polymorphisms (SNPs) in ADAM17 and other TGF-β signaling pathway genes including TGFB2 and SMAD3, on KD phenotypes relative to single SNPs suggest that ADAM17 is also involved in secondary CAL formation and confers the risk of KD/CALs via the TGF-β/SMAD3 signaling pathway.

Topics: ADAM17 Protein; Child, Preschool; Coronary Artery Disease; Coronary Vessels; DNA; Female; Genetic Predisposition to Disease; Genotype; Humans; Infant; Male; Mucocutaneous Lymph Node Syndrome; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

Neointima forming after stent implantation consists of vascular smooth muscle cells (VSMCs) in 90%. Growth factors TGF-β1, PDGFB, EGF, bFGF and VEGF-A play an important role in VSMC proliferation and migration to the tunica intima after arterial wall injury. The aim of this paper was an analysis of functional polymorphisms in genes encoding TGF-β1, PDGFB, EGF, bFGF and VEGF-A in relation to in-stent restenosis (ISR).. 265 patients with a stable coronary artery disease (SCAD) hospitalized in our center in the years 2007-2011 were included in the study. All patients underwent stent implantation at admission to the hospital and had another coronary angiography performed due to recurrence of the ailments or a positive result of the test assessing the coronary flow reserve. Angiographically significant ISR was defined as stenosis >50% in the stented coronary artery segment. The patients were divided into two groups-with angiographically significant ISR (n = 53) and without significant ISR (n = 212). Additionally, the assessment of late lumen loss (LLL) in vessel was performed. EGF rs4444903 polymorphism was genotyped using the PCR-RFLP method whilst rs1800470 (TGFB1), rs2285094 (PDGFB) rs308395 (bFGF) and rs699947 (VEGF-A) were determined using the TaqMan method.. Angiographically significant ISR was significantly less frequently observed in the group of patients with the A/A genotype of rs1800470 polymorphism (TGFB1) versus patients with A/G and G/G genotypes. In the multivariable analysis, LLL was significantly lower in patients with the A/A genotype of rs1800470 (TGFB1) versus those with the A/G and G/G genotypes and higher in patients with the A/A genotype of the VEGF-A polymorphism versus the A/C and C/C genotypes. The C/C genotype of rs2285094 (PDGFB) was associated with greater LLL compared to C/T heterozygotes and T/T homozygotes.. The polymorphisms rs1800470, rs2285094 and rs6999447 of the TGFB1, PDGFB and VEGF-A genes, respectively, are associated with LLL in patients with SCAD treated by PCI with a metal stent implantation.

Topics: Aged; Coronary Artery Disease; Coronary Restenosis; Epidermal Growth Factor; Female; Fibroblast Growth Factor 2; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins c-sis; Stents; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Coronary artery disease (CAD) and hypertension are the main reasons of ischemic heart diseases (IHDs). Cytokines as the small glycoproteins are the main arm of immune system and manipulate all of the cardiovascular diseases. The aim of the current study was to examine the effects of treatment of hypertension and CAD on serum levels of IL-6, IL-8, TGF-β and TNF-α.. This interventional study was performed on the patients with hypertension without CAD (group 1), hypertension and CAD (group 2), CAD but not hypertension (group 3) and without hypertension and CAD as controls (group 4). The patients received routine treatment for hypertension and CAD. Serum levels of IL-6, IL-8, TGF-β and TNF-α were analyzed in the groups treated with various drugs, using ELISA technique.. With regard to the medications, Atorvastatin, Losartan and Captopril were administered more in patients (groups 1, 2 and 3) than the patients without hypertension and CAD. The results revealed that serum levels of TGF-β and IL-6 were significantly increased and decreased, respectively, in the groups 1, 2 and 3 when compared to group 4. Serum levels of TGF-β were also increased in females in comparison to males in the group 4.. According to the results it seems that Atorvastatin, Losartan and Captopril have reduced inflammation in in vivo conditions via downregulation of IL-6 and upregulation of TGF-β.

Topics: Antihypertensive Agents; Atorvastatin; Captopril; Coronary Artery Disease; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Inflammation; Interleukin-6; Interleukin-8; Iran; Losartan; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Up-Regulation

We assessed the association between 5 well-defined polymorphisms of the transforming growth factor-β1 (TGFB1) gene and coronary artery disease (CAD) among patients with hypertension from northeast China. All study participants were classified into patients with CAD (n = 679) and controls (n = 686) according to angiographic results. Genotyping was carried out with the ligase detection reaction method. In single-locus analysis, only genotypes of rs1800469 differed significantly between patients with CAD and controls (P = .001); patients carrying the mutant allele of rs1800469 exhibited a 73% increased risk of CAD (P < .001). Haplotype analysis indicated that haplotype A-T-T-C-C (alleles in the order of rs1800468, rs1800469, rs1800470, rs1800471, and rs1800472) was associated with a 1.49-fold increased risk (P = .003). Interaction analysis identified an overall best 3-locus model including rs1800469, rs1800468, and rs1800471 (P = .003). Taken together, we identified a synergistic interaction between TGFB1 gene multiple polymorphisms that entailed greater risk of CAD in Chinese patients.

Topics: Aged; Alleles; Biomarkers; Case-Control Studies; China; Coronary Angiography; Coronary Artery Disease; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Hypertension; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Transforming Growth Factor beta

The COL4A1/COL4A2 region on chromosome 13q34 is a highly replicated locus for coronary artery disease (CAD). In the normal arterial wall, type IV collagen acts to inhibit smooth muscle cell proliferation. Its production is in part a function of TGFβ signaling, but the specific regulatory mechanisms, especially in humans, have not been defined. Our aim was to decipher TGFβ signaling components important in the regulation of COL4A1 and COL4A2 and determine whether these components showed genetic interaction with the COL4A1/COL4A2 locus for CAD association.. Experiments were performed in primary human aortic smooth muscle cells and HT1080 fibroblasts. Pharmacological inhibition of the TGFβ1 receptor and subsequent SMAD protein phosphorylation by treatment with an ALK5 inhibitor prevented the increase in COL4A1/COL4A2 mRNA (p < 0.001) and protein expression in response to TGFβ1 stimulation. In contrast, inhibition of the non-canonical TGFβ signaling pathways was without effect. siRNA mediated knockdown of SMAD3 and SMAD4 abolished the stimulatory effects of TGFβ1 on COL4A1/COL4A2 (p < 0.001) whereas SMAD2 knockdown had no effect. In luciferase reporter assays, neither SMAD3 overexpression nor TGFβ1 treatment altered COL4A1 or COL4A2 promoter activity, supportive of more complex regulation of type IV collagen gene expression by the TGFβ/SMAD3 signaling pathway. Epistasis analysis in 5 CAD case/control cohorts revealed that SMAD3 and COL4A1/COL4A2 display statistical interaction for CAD association.. These findings demonstrate that SMAD3 is a necessary factor for TGFβ-mediated stimulation of mRNA and protein expression of type IV collagen genes in human vascular smooth muscle cells. Epistasis analyses further supports the hypothesis that the SMAD3-dependent regulation of COL4A1/COL4A2 may be of functional significance for CAD pathogenesis.

Topics: Aorta; Cell Line; Cohort Studies; Collagen Type IV; Coronary Artery Disease; Enzyme Inhibitors; Epistasis, Genetic; Fibroblasts; Gene Expression Regulation; Genes, Reporter; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; RNA, Small Interfering; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta; Up-Regulation

The molecular mechanisms responsible for the development and progression of atherosclerotic lesions have not been fully established. Here, we investigated the role played by endothelial-to-mesenchymal transition (EndMT) and its key regulator FGF receptor 1 (FGFR1) in atherosclerosis. In cultured human endothelial cells, both inflammatory cytokines and oscillatory shear stress reduced endothelial FGFR1 expression and activated TGF-β signaling. We further explored the link between disrupted FGF endothelial signaling and progression of atherosclerosis by introducing endothelial-specific deletion of FGF receptor substrate 2 α (Frs2a) in atherosclerotic (Apoe(-/-)) mice. When placed on a high-fat diet, these double-knockout mice developed atherosclerosis at a much earlier time point compared with that their Apoe(-/-) counterparts, eventually demonstrating an 84% increase in total plaque burden. Moreover, these animals exhibited extensive development of EndMT, deposition of fibronectin, and increased neointima formation. Additionally, we conducted a molecular and morphometric examination of left main coronary arteries from 43 patients with various levels of coronary disease to assess the clinical relevance of these findings. The extent of coronary atherosclerosis in this patient set strongly correlated with loss of endothelial FGFR1 expression, activation of endothelial TGF-β signaling, and the extent of EndMT. These data demonstrate a link between loss of protective endothelial FGFR signaling, development of EndMT, and progression of atherosclerosis.

Topics: Adaptor Proteins, Signal Transducing; Animals; Apolipoproteins E; Coronary Artery Disease; Human Umbilical Vein Endothelial Cells; Humans; Membrane Proteins; Mice; Mice, Knockout; Receptor, Fibroblast Growth Factor, Type 1; Transforming Growth Factor beta

FTY720, an analogue of sphingosine-1-phosphate, is cardioprotective during acute injury. Whether long-term FTY720 affords cardioprotection is unknown. Here, we report the effects of oral FTY720 on ischemia/reperfusion injury and in hypomorphic apoE mice deficient in SR-BI receptor expression (ApoeR61(h/h)/SRB1(-/- mice), a model of diet-induced coronary atherosclerosis and heart failure. We added FTY720 (0.3 mg·kg(-1)·d(-1)) to the drinking water of C57BL/6J mice. After ex vivo cardiac ischemia/reperfusion injury, these mice had significantly improved left ventricular (LV) developed pressure and reduced infarct size compared with controls. Subsequently, ApoeR61(h/h)/SRB1(-/-) mice fed a high-fat diet for 4 weeks were treated or not with oral FTY720 (0.05 mg·kg(-1)·d(-1)). This sharply reduced mortality (P < 0.02) and resulted in better LV function and less LV remodeling compared with controls without reducing hypercholesterolemia and atherosclerosis. Oral FTY720 reduced the number of blood lymphocytes and increased the percentage of CD4+Foxp3+ regulatory T cells (Tregs) in the circulation, spleen, and lymph nodes. FTY720-treated mice exhibited increased TGF-β and reduced IFN-γ expression in the heart. Also, CD4 expression was increased and strongly correlated with molecules involved in natural Treg activity, such as TGF-β and GITR. Our data suggest that long-term FTY720 treatment enhances LV function and increases longevity in mice with heart failure. These benefits resulted not from atheroprotection but from systemic immunosuppression and a moderate reduction of inflammation in the heart.

Topics: Animals; Apolipoproteins E; Cardiotonic Agents; Coronary Artery Disease; Diet, High-Fat; Disease Models, Animal; Fingolimod Hydrochloride; Immunosuppressive Agents; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardial Reperfusion Injury; Propylene Glycols; Sphingosine; Survival Rate; T-Lymphocytes, Regulatory; Time Factors; Transforming Growth Factor beta; Ventricular Function, Left

The Arf tumor suppressor represents one of several genes encoded at the Cdkn2a and Cdkn2b loci in the mouse. Beyond its role blunting the growth of incipient cancer cells, the Arf gene also plays an essential role in development: its gene product, p19(Arf), is induced by Tgfβ2 in the developing eye to dampen proliferative signals from Pdgfrβ, which effect ultimately fosters the vascular remodeling required for normal vision in the mouse. Mechanisms underlying Arf induction by Tgfβ2 are not fully understood. Using the chr4(Δ70 kb/Δ70 kb) mouse, we now show that deletion of the coronary artery disease (CAD) risk interval lying upstream of the Cdkn2a/b locus represses developmentally-timed induction of Arf resulting in eye disease mimicking the persistent hyperplastic primary vitreous (PHPV) found in Arf-null mice and in children. Using mouse embryo fibroblasts, we demonstrate that Arf induction by Tgfβ is blocked in cis to the 70 kb deletion, but Arf induction by activated RAS and cell culture "shock" is not. Finally, we show that Arf induction by Tgfβ is derailed by preventing RNA polymerase II recruitment following Smad 2/3 binding to the promoter. These findings provide the first evidence that the CAD risk interval, located at a distance from Arf, acts as a cis enhancer of Tgfβ2-driven induction of Arf during development.

Topics: ADP-Ribosylation Factor 1; Animals; Coronary Artery Disease; Disease Models, Animal; DNA, Intergenic; Enhancer Elements, Genetic; Eye; Eye Diseases; Fibroblasts; Gene Deletion; Gene Expression Regulation, Developmental; Mice; Mice, Transgenic; Persistent Hyperplastic Primary Vitreous; Phenotype; Receptor, Platelet-Derived Growth Factor beta; Time Factors; Transforming Growth Factor beta

To examine the single nucleotide polymorphism (SNP) (rs1495592) in transforming growth factor-beta receptor 2 (TGFBR2) gene in children, and to investigate its association with Kawasaki disease (KD) and coronary artery lesions (CALs).. Thirty-five KD patients, 14 of whom had CALs (CAL subgroup), were selected as the case group, and 25 healthy age-matched children were selected as the control group. The SNP (rs1495592) in TGFBR2 gene was studied by gene sequencing. The association of SNP (rs1495592) with KD and (CALs) was analyzed based on the sequencing results.. There were no significant differences in genotype frequency distribution (χ(2)=0.566, P=0.452) and allele frequency distribution (χ(2)=0.216, P=0.642) between the two groups. Genotypes in the CAL subgroup included CC (21.4%) and CT+TT (78.6%), while genotypes in the non-CAL subgroup included CC (61.9%) and CT+TT (38.1%). There was significant difference in genotype frequency distribution between the two groups (χ(2)=5.546, P=0.019), but without significant difference in allele frequency distribution (χ(2)=3.673, P=0.055).. The SNP (rs1495592) in TGFBR2 gene may not be associated with development of KD in children, but it is associated with CALs in children with KD.

Topics: Coronary Artery Disease; Female; Genetic Predisposition to Disease; Genotype; Humans; Infant; Male; Mucocutaneous Lymph Node Syndrome; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Transforming Growth Factor beta

Kawasaki disease (KD) is an acute inflammatory illness marked by coronary arteritis. However, the factors increasing susceptibility to coronary artery lesions are unknown. Because transforming growth factor (TGF) β increases elastin synthesis and suppresses proteolysis, we hypothesized that, in contrast to the benefit observed in aneurysms forming in those with Marfan syndrome, inhibition of TGF-β would worsen inflammatory-induced coronary artery lesions. By using a murine model of KD in which injection of Lactobacillus casei wall extract (LCWE) induces coronary arteritis, we show that LCWE increased TGF-β signaling in the coronary smooth muscle cells beginning at 2 days and continuing through 14 days, the point of peak coronary inflammation. By 42 days, LCWE caused fragmentation of the internal and external elastic lamina. Blocking TGF-β by administration of a neutralizing antibody accentuated the LCWE-mediated fragmentation of elastin and induced an overall loss of medial elastin without increasing the inflammatory response. We attributed these increased pathological characteristics to a reduction in the proteolytic inhibitor, plasminogen activator inhibitor-1, and an associated threefold increase in matrix metalloproteinase 9 activity compared with LCWE alone. Therefore, our data demonstrate that in the coronary arteritis associated with KD, TGF-β suppresses elastin degradation by inhibiting plasmin-mediated matrix metalloproteinase 9 activation. Thus, strategies to block TGF-β, used in those with Marfan syndrome, are unlikely to be beneficial and could be detrimental.

Topics: Animals; Cell Wall; Collagen Type I; Complex Mixtures; Coronary Artery Disease; Coronary Vessels; Disease Models, Animal; Elastin; Lacticaseibacillus casei; Matrix Metalloproteinase 9; Mice; Mucocutaneous Lymph Node Syndrome; Plasminogen Activator Inhibitor 1; Protein Processing, Post-Translational; Signal Transduction; Transforming Growth Factor beta; Tropoelastin

Th17 cells producing IL-17 are involved in the pathogenesis of atherosclerosis, but the underlying mechanisms remain unclear. In this study, we investigated the effects of IL-17 on human vascular endothelial cells and showed that IL-17 induced cell death of the vascular endothelial cells, which played a pivotal role in plaque destabilization triggering acute coronary syndrome (ACS). We showed that circulating Th17 cells and IL-17 increased in patients with ACS compared to the patients with stable angina or health individuals; the plasma levels of IL-6 increased but TGF-β decreased in ACS patients, exhibiting a positive and negative correlation with that of IL-17, respectively. Importantly, we uncovered that IL-17 promoted the production of von Willebrand factor by endothelial cells and induced endothelial apoptosis by activating caspase-3, caspase-9 and up-regulating the ratio of Bax/Bcl-2, indicating the function of IL-17 in vascular endothelial damage as a potential mechanism for the pathogenesis of human ACS.

Topics: Acute Coronary Syndrome; Angina, Stable; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Caspase 9; Cells, Cultured; Coronary Artery Disease; Endothelial Cells; Female; Gene Expression Regulation; Humans; Interleukin-17; Interleukin-6; Male; Middle Aged; Proto-Oncogene Proteins c-bcl-2; Recombinant Proteins; Th17 Cells; Transforming Growth Factor beta; Up-Regulation; von Willebrand Factor

Extracellular matrix (ECM) accumulation significantly contributes to in-stent restenosis. In this regard, transforming growth factor (TGF)-β, a positive regulator of ECM deposition, may be implicated in in-stent restenosis. The goal of this study was to assess the effect of blockade of TGF-β on stent-induced restenosis in porcine coronary arteries.. An adenovirus expressing the ectodomain of the TGF-β type II receptor (AdTβ-ExR) was applied onto a coronary arterial segment of a pig (n=10) using an Infiltrator, followed by stent deployment. Controls consisted of adenoviruses expressing β-galactosidase (AdLacZ) or phosphate-buffered saline (PBS) applied onto the other segment (n=10) of the same pig.. Computer-based pathological morphometric analysis of stented coronary arteries, performed 4 weeks after stenting, demonstrated no significant difference in morphometric parameters such as in-stent neointimal area and % area stenosis between the AdTβ-ExR group and control (n=7 for each). However the AdTβ-ExR group had increased neointimal cell density, infiltration of inflammatory cells mostly consisting of CD3+ T cell, accumulation of hyaluronan, cell proliferation rate, and adventitial matrix metalloproteinase-1 (MMP-1) expression compared with control. The expression of connective tissue growth factor mRNA, measured by reverse transcription PCR, in cultured rat arterial smooth muscle cells was inhibited by AdTβ-ExR at moi 60.. Blockade of TGF-β by catheter-based local intravascular gene delivery does not reduce stent-induced neointima formation 4 weeks after stenting in spite of modest inhibition of ECM accumulation, but it induces vascular inflammation and associated pathological changes that may potentially aggravate lesion progression.

Topics: Angioplasty; Animals; Catheterization; CD3 Complex; Cells, Cultured; Connective Tissue Growth Factor; Coronary Artery Disease; Female; Gene Transfer Techniques; Hyaluronic Acid; In Vitro Techniques; Male; Matrix Metalloproteinase 1; Muscle, Smooth, Vascular; Neointima; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Stents; Swine; T-Lymphocytes; Transforming Growth Factor beta

Topics: Coronary Artery Disease; Ectodysplasins; Fibronectins; Humans; Psoriasis; Streptococcus; Transforming Growth Factor beta

Activin-like kinase receptor 1 (ALK1) is a transforming growth factor (TGF)-beta type I receptor expressed in vascular mesenchyme, yet its function in vascular mesenchymal cells (VMC) is unclear. We examined ALK1 expression in human coronary atherosclerotic lesions and bovine and human VMC undergoing cellular condensation in vitro. We also examined the effect of activated ALK1 on cell proliferation and smooth muscle cell (SMC) differentiation.. Our results showed that ALK1 was expressed in human coronary atherosclerotic lesions as determined by immunohistochemistry. ALK1 was also expressed in cellular condensations of bovine and human VMC as determined by real-time PCR and immunocytochemistry. Bone morphogenetic protein (BMP)-2, which is known to increase condensation size, increased ALK1 expression when induced from a BMP-2 adenoviral vector. In turn, activated ALK1 induced expression of matrix GLA protein (MGP), a BMP-2 inhibitor known to limit condensation size. Activated ALK1 enhanced proliferation of VMC as determined by 3H-thymidine incorporation, whereas MGP decreased proliferation. Activated ALK1 also enhanced expression of SMC lineage markers and ALK5, another TGF-beta type I receptor, as determined by immunoblotting, real-time PCR and immunocytochemistry. Anti-TGF-beta antibodies abolished expression of SMC markers in the presence of constitutively active ALK1, suggesting that ALK1 activation alone is not sufficient to promote SMC differentiation.. We conclude that there is a balance between the actions of BMP-2 and MGP in the initiation of vascular mesenchymal cell condensation and SMC differentiation, and that targeting ALK1, BMP2 and/or MGP may lead to novel concepts of atherosclerosis treatment.

Topics: Activin Receptors, Type I; Activin Receptors, Type II; Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Calcium-Binding Proteins; Cattle; Cell Differentiation; Cell Line; Cell Proliferation; Cells, Cultured; Coronary Artery Disease; Coronary Vessels; Extracellular Matrix Proteins; Humans; Immunohistochemistry; Matrix Gla Protein; Mesoderm; Myocytes, Smooth Muscle; Transduction, Genetic; Transforming Growth Factor beta

Coronary calcification is a potent predictor of cardiac events. In patients with chronic renal disease, both prevalence and intensity of coronary calcification are increased. It has remained uncertain whether it is the intima of the coronaries or the media that is calcified and whether the morphologic details of calcified plaques differ between renal and nonrenal patients. Autopsy samples of coronaries were obtained from standard sites in 23 renal and 23 age- and gender-matched nonuremic patients. Specimens were examined using light and electron microscopy, immunohistochemistry, backscatter imaging, and x-ray analysis. In coronaries, calcified plaques occupied a similar proportion of the intima area in renal versus nonrenal patients (17.3 +/- 11.9 versus 18.1 +/- 11.9%) but occupied a significantly higher proportion of the media (16.6 +/- 10.6 versus 3.8 +/- 2.31%). Expression of the proteins osteocalcin, C-reactive protein, TGF-beta, and collagen IV was significantly more intensive around coronary plaques of renal compared with nonrenal patients. The non-plaque-bearing intima of renal patients showed minimal staining for fetuin, but fetuin staining was seen surrounding calcified plaques. In addition, more pronounced deposition of C5b-9 was found around coronary plaques of renal patients, and glycophorin deposition pointed to more past intraplaque hemorrhage in renal patients. Calcification by electron backscatter analysis is more intense in the coronary media, but not if the intima is more intense in renal compared with nonrenal patients. A more marked inflammatory response in renal patients is suggested by more frequent presence and greater intensity of markers of inflammation.

Topics: Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Calcinosis; Collagen Type IV; Complement Membrane Attack Complex; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Endothelium, Vascular; Female; Glycophorins; Humans; Hypoxia; Immunohistochemistry; Kidney Diseases; Macrophages; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Middle Aged; Transforming Growth Factor beta; Tunica Intima; Tunica Media

Studies to define the overall contribution of lymphocytes to lesion formation in atherosclerosis-susceptible mice have demonstrated relatively subtle effects; the use of lymphocyte-deficient mice, however, compromises both the effector and regulatory arms of the immune system. Here, we tested the hypothesis that deletion of CXCL10 (IP-10), a chemokine specific for effector T cells that has been localized within atherosclerotic lesions, would significantly inhibit atherogenesis.. Compound deficient Apoe(-/-)/Cxcl10(-/-) mice fed a Western-style diet for either 6 or 12 weeks demonstrated significant reductions in atherogenesis as compared with Apoe(-/-) controls, as assessed by both aortic en face and cross-sectional analyses. Immunohistochemical studies revealed a decrease in the accumulation of CD4+ T cells, whereas quantitative polymerase chain reaction analysis of lesion-rich aortic arches demonstrated a marked reduction in mRNA for CXCR3, the CXCL10 chemokine receptor. Although overall T-cell accumulation was diminished significantly, we found evidence to suggest that regulatory T-cell (Treg) numbers and activity were enhanced, as assessed by increased message for the Treg-specific marker Foxp3, as well as increases in immunostaining for the Treg-associated cytokines interleukin-10 and transforming growth factor-beta1. We also documented naturally occurring Treg cells in human atherosclerotic lesions.. We provide novel evidence for a functional role for the effector T-cell chemoattractant CXCL10 in atherosclerotic lesion formation by modulating the local balance of the effector and regulatory arms of the immune system.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Chemokine CXCL10; Chemokines, CXC; Coronary Artery Disease; Coronary Vessels; Flow Cytometry; Forkhead Transcription Factors; Immunohistochemistry; Interleukin-10; Mice; Mice, Mutant Strains; Polymerase Chain Reaction; Receptors, Chemokine; Receptors, CXCR3; RNA, Messenger; Signal Transduction; T-Lymphocytes; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Coronary Artery Disease; Disease Progression; Humans; Immune System; Interferon-gamma; Lipoproteins, LDL; T-Lymphocytes; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Vaccines

It is well documented that inflammation plays a major role in the establishment and progression of atherosclerosis. Endothelial cells, vascular smooth muscle cells and monocytes/macrophages are involved in this process by expressing inflammatory factors. The aim of the present study was to evaluate potential association and risk of VEGF-A and TGF-beta1 in human coronary atherosclerotic lesions. Twenty-six fresh human coronary artery segments were collected at autopsy. Conventional histology was performed and samples were classified into: no lesion group (NL), fatty streak group (FS), plaque group (P) and complicated lesion group (CL) based on the atherosclerotic lesion type. RNA extraction-analysis with RT-PCR and immunohistochemistry was also performed. We observed that VEGF-A protein and mRNA expression increased during atherogenesis. The expression levels (protein and mRNA levels) of TGF-beta1 were decreased from NL to the FS group while, strong protein-staining and signal of mRNA expression in P and CL groups were observed. Our findings suggest a crucial role of VEGF-A in the development of coronary artery disease. The high protein and mRNA expression levels of TGF-beta1 in P and CL suggest that this factor may be implicated in the deposition of excessive extracellular matrix in the intima of the vessel wall, contributing to the expansion of the atheromatic plaque.

Topics: Adult; Aged; Aged, 80 and over; Coronary Artery Disease; Coronary Vessels; Female; Humans; Immunohistochemistry; Male; Middle Aged; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

To explore whether local growth factors concentration, including vascular endothelial growth factor (VEGF) and transforming growth factor beta one (TGF-beta(1)), influence the formation of coronary collaterals.. Thirty-six patients scheduled for coronary angiography received a 6F Goodale-Lubin catheterization to collect blood from the coronary sinus (CS) and right atrium (RA).. Patients with coronary collaterals had a higher number of diseased vessels (2.6+/-0.2 vs. 1.4+/-0.3, p = 0.005), higher percentage of severity of stenosis (93+/-2 vs. 48+/-8, P < 0.001) and higher VEGF concentrations in CS (38.9+/-3.9 pg/ml vs. 20.8+/-1.4 pg/ml, P < 0.001) and in RA (31.7+/-3.1 pg/ml vs. 22.0+/-2.3 pg/ml, p = 0.004). There was no significant relationship between coronary collateral formation and TGF-beta(1) concentration. By binary logistic regression analysis, VEGF concentrations in CS (p = 0.030) and stenosis severity (p = 0.042) are correlated positively with collateral formation.. The association between local, endogenous secretion of VEGF and coronary collateral formation is compatible with a paracrine role for this growth factor in pathophysiologic collateral formation.

Topics: Collateral Circulation; Coronary Artery Disease; Coronary Stenosis; Coronary Vessels; Female; Humans; Male; Middle Aged; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vascular Endothelial Growth Factors

Coronary vasculopathy (CV) is an important determinant of survival following cardiac transplantation. We have previously shown that G915C polymorphism of the Transforming Growth Factor-beta1 (TGF-beta1) gene strongly influences CV development. Furin is a proprotein convertase enzyme important in TGF-beta1 activation. We investigated for polymorphism within the promoter region of the gene for furin (fur). Allelic variation of the fur gene, in conjunction with TGF-beta1 polymorphism, was subsequently related to the development of CV.. The fur gene promoter region (position -1199 to +39) was analysed by SSCP and sequencing. A C/T single nucleotide substitution polymorphism at position -231* was identified. Using PCR the fur and TGFB1 genotypes were identified in 115 cardiac transplant recipients. CV was diagnosed at routine surveillance post-transplant coronary angiography. Fur polymorphism had no influence on vasculopathy development; median time to diagnosis, *C/C homozygotes, 2.27 years (2.10-4.32), *C/T heterozygotes 2.97 years (2.09-4.24), *T/T homozygotes 2.65 years (2.33-4.08), (P=0.95). Allelic variation did not influence Kaplan Meier actuarial analysis of disease onset (P=0.54). Ninety-three percent of recipients were high TGF-beta1 producers. We used fur polymorphism to substratify patients with the +915*G/G TGFB1 (high producing) allele. Fur polymorphism did not influence CV development within this TGF-beta1 high producer cohort, when analysed by time to first diagnosis and Kaplan Meier testing.. We have described a novel polymorphism at position -231* in the gene encoding furin. The fur -231* single nucleotide polymorphism in isolation, or in conjunction with TGFB1 polymorphism, is not useful as a genetic risk marker for cardiac transplant associated coronary vasculopathy.

Topics: Adult; Coronary Angiography; Coronary Artery Disease; Female; Furin; Heart Transplantation; Humans; Male; Middle Aged; Polymorphism, Genetic; Promoter Regions, Genetic; Retrospective Studies; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transplantation, Homologous; United Kingdom

Transforming growth factor-beta1 (TGF-beta1) has been implicated in the pathogenesis of coronary vasculopathy following cardiac transplantation. The TGFB1 gene contains polymorphisms at positions +915* (Arg25Pro) and +869* (Leu10Pro) which may influence TGF-beta1 expression. We investigated the relationship between the development of coronary vasculopathy and the prevalence of these alleles in a cardiac transplant population.. Vasculopathy was diagnosed at routine surveillance post-transplant coronary angiography. Using sequence-specific polymerase chain reaction we identified the TGFB1 +915* and +869* genotypes in 147 cardiac transplant recipients and 134 cardiac donors.. TGFB1 +915*C allele carriers (low producers) made up 10.5% of the recipient population but were significantly less likely to develop coronary vasculopathy (P=0.03). Median time to diagnosis was 6.0 years (3.9-8.72) in +915*C allele carriers compared to 2.75 years (2.10-4.22) in *G/G homozygotes (p=0.002). Pre- and 1 year post-transplant clinical variables were equivalent between the two groups. Multivariate analysis identified the recipient +915*G/G genotype (hazard ratio 2.96 (95% CI, 1.09-9.98); p=0.039), donor age (hazard ratio 1.05 (95% CI, 1.02-1.09); p=0.008) and number of acute rejection episodes of ISHLT grade 3 or greater in the first year (hazard ratio 1.12 (95% CI, 1.01-1.23); p=0.03) as significant predictors of vasculopathy. The recipient TGFB1 +869*, and both alleles in the donor, had no influence on vasculopathy development.. Recipient TGFB1 +915* genotype influences the development of cardiac transplant-related coronary vasculopathy. This gives an important insight to the pathophysiology of the disease. On the contrary, donor TGFB1 +915* and TGFB1 +869* polymorphisms do not appear to be important and cannot be used as genetic risk factors.

Topics: Coronary Angiography; Coronary Artery Disease; Genotype; Heart Transplantation; Humans; Immunosuppression Therapy; Perioperative Care; Polymerase Chain Reaction; Polymorphism, Genetic; Risk Factors; Tissue Donors; Transforming Growth Factor beta; Transforming Growth Factor beta1; United Kingdom

Coronary arterial lesions (CAL) due to Kawasaki disease (KD) often show progressive intimal hyperplasia even many years after the disease. However, most patients have no CAL after the acute phase, and it is an important issue whether or not coronary arteries without CAL have significant intimal hyperplasia, and whether or not there is the potential for this to progress to stenosis and/or atherosclerosis.. The authors examined formalin-fixed specimens of the coronary arteries immunohistochemically, using antibodies against vascular growth factors (GFs), the receptors of transforming growth factor-beta (TbetaRs) and inducible nitric oxid synthesis (iNOS) in a KD patient without CAL, and also in four control patients: two with CAL due to KD and two without a history of KD.. Vascular endothelial GFs, Platelet-derived growth factor-A (PDGF-A) and TbetaRs were expressed in the vascular smooth muscle cells of all patients. PDGF-A, transforming Gfbeta1 and iNOS were expressed in the intimal smooth muscle cells of the KD but not the normal coronary artery without a history of KD. The number of TbetaR-II-positive cells were fewer than TbetaR-I-positive cells in the intima of CAL due to KD, but the number was of both almost same in the intima of coronary artery without CAL after KD and in the normal coronary.. The intact coronary artery 13 months after KD still showed the influence of the inflammation of KD. Although the authors speculate that the intimal proliferation will not continue beyond the acute phase, those patients may have a risk factor for atherosclerosis.

Topics: Child, Preschool; Coronary Artery Disease; Coronary Vessels; Humans; Immunohistochemistry; Infant; Mucocutaneous Lymph Node Syndrome; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Platelet-Derived Growth Factor; Receptors, Transforming Growth Factor beta; Time Factors; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Myocardial fibrosis contributes to the impairing of cardiac function and characterizes ageing, but is also a consequence of atherosclerotic ischemic disease. Since atherosclerosis is a slow progressive disease, which prevails in elderly populations, the aim of this study was to distinguish the contribution of ageing and atherosclerosis to cardiac fibrosis.. Coronary atherosclerosis was induced in 5-6-year-old rabbits by a hyperlipemic diet for 9 months. Left ventricular (LV) collagen was quantified by densitometric analysis after Sirius-Red staining; an immunohistochemical investigation of the interstitium was also performed.. Atherosclerosis was associated to a marked increase of left ventricular interstitial collagen with the appearance of fibrotic foci and a decrease of coronary vessel endothelial nitric oxide synthase (eNOS) expression. In fibrotic foci, abundant macrophages co-localized with transforming growth factor beta-1 (TGFbeta-1)-positive myofibroblasts and vascular cell adhesion molecule-1 (VCAM-1) positive microvessels (52.3+/-3.9%). In normocholesterolemic rabbits, ageing resulted in a fourfold increase of myocardial interstitial collagen, with alpha-smooth muscle actin and TGFbeta-1 negative fibroblasts and VCAM-1 positive microvessels (19.4+/-1.2%) without macrophages, suggesting a role of endothelial dysfunction in age-related fibrosis.. There is a distinct difference between ageing and coronary atherosclerosis-induced cardiac fibrosis, although the effects may be cumulative. In the cascade of events leading to myocardial remodeling, reparative fibrosis with TGFbeta-1-positive myofibroblasts and interstitial inflammation were the major findings in atherosclerotic old rabbits, whereas with ageing alone, interstitial fibrosis with TGFbeta-1 negative fibroblasts and VCAM-1 positive microvessels prevailed.

Topics: Actins; Aging; Animals; Cell Count; Coronary Artery Disease; Coronary Vessels; Endothelium, Vascular; Extracellular Matrix; Fibrosis; Immunohistochemistry; In Situ Nick-End Labeling; Male; Myocytes, Cardiac; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Rabbits; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1

Transforming growth factor-beta (TGF-beta) and matrix metalloproteinases-9 (MMP-9) have been implicated in the pathogenesis of human atherosclerosis but their relationship during lesion progression are poorly understood. The objective of this study was to investigate the expression of MMP-9, TGF-beta1 and TGF-beta receptor I (TbetaR-I) in human atherosclerotic plaque and their relationship and plaque stability.. Specimens of human coronary artery atherosclerotic plaques were obtained from 41 patients undergoing coronary endarterectomy, and were paraffin embedded, sectioned at 4 microm intervals then stained with haematoxylin and eosin. They were divided into stable (with no or only little lipid core) and unstable plaque groups (with lipid core size > 40%): the immunohistochemical staining were performed for MMP-9, TGF-beta1 and TbetaR-I.. The expression of MMP-9 in the unstable plaques was much higher than in the stable ones, but the expression of TGF-beta1 was higher in the stable plaques. There was no similar significant difference for TbetaR-I. Correlation analysis showed that there was a negative correlation between the expression of MMP-9 and TGF-beta1 (r = -0.332, P = 0.034 for average areal density; r = -0.373, P = 0.016 for average optical density).. There were close relationships between MMP-9, TGF-beta1 and plaque stability. Enhanced production of MMP-9 may participate in the formation of unstable plaque, while TGF-beta1 maybe an important stabilizing factor in preventing transition into an unstable plaque phenotype.

Topics: Activin Receptors, Type I; Coronary Artery Disease; Extracellular Matrix; Female; Humans; Immunohistochemistry; Male; Matrix Metalloproteinase 9; Middle Aged; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta; Transforming Growth Factor beta1

Cytokines play an important role in modulating inflammatory and proliferative responses, including atherosclerosis. Transforming growth factor-beta (TGF-beta) and macrophage-colony stimulating factor (M-CSF) are one of the major antiinflammatory and proinflammatory cytokines, respectively. We have previously demonstrated that plasma concentrations of TGF-beta are decreased while those of M-CSF are increased in patients with coronary artery disease (CAD). In this study, we examined whether those alterations in plasma levels of cytokines have a prognostic significance in patients with CAD.. Sixty-eight consecutive patients with proven CAD were studied. The plasma concentrations of TGF-beta and those of M-CSF were measured by enzyme-linked immunosorbent assay (ELISA). They were divided into groups: high (> or =6 ng/ml, n = 19) and low (<6 ng/ml, n = 49) TGF-beta groups and high (>500 ng/ml, n = 52) and low (< or =500 ng/ml, n = 16) M-CSF groups. The long-term prognosis of these patients was prospectively followed up for a mean period of 979 +/- 27 days. The prognosis was analyzed by Kaplan-Meier analysis in terms of total survival, survival without myocardial infarction, survival without cardiovascular events and survival without coronary interventions. The analysis showed that the low TGF-beta group had a significantly poor prognosis in terms of survival without cardiovascular events and survival without coronary interventions as compared with the high TGF-beta group (both P < 0.05), while other prognoses were comparable between the two groups. By contrast, no significant prognostic influence was noted regarding M-CSF.. These results suggest that plasma concentrations of TGF-beta may have a prognostic significance in patients with CAD.

Topics: Aged; Biomarkers; Coronary Artery Disease; Female; Follow-Up Studies; Humans; Macrophage Colony-Stimulating Factor; Male; Middle Aged; Prognosis; Prospective Studies; Survival Analysis; Time Factors; Transforming Growth Factor beta

The major cause of morbidity and mortality after cardiac transplantation is cardiac allograft vasculopathy (CAV). The purpose of this study was to examine the expression of markers of endothelial injury that may be affected by blood/insulin or crystalloid cardioplegia. After RNA-blot hybridization, the level of expression of tumor necrosis factor-alpha, transforming growth factor-beta (TGF-beta), intracellular adhesion molecule-1, platelet-endothelial cell adhesion molecule-1, endothelin-1, and E-selectin was increased in crystalloid cardioplegia as compared with normal and blood/insulin cardioplegia; TGF-beta was expressed at significantly lower levels in blood/insulin vs crystalloid cardioplegia (p < 0.05). Because increased expression of TGF-beta has been correlated with accelerated CAV, the use of blood/insulin cardioplegia may help to decrease the extent of endothelial damage and attenuate the progression of CAV.

Topics: Cardioplegic Solutions; Coronary Artery Disease; Heart Arrest, Induced; Heart Transplantation; Humans; Insulin; Myocardium; Organ Preservation Solutions; Postoperative Complications; Potassium Compounds; RNA; Transforming Growth Factor beta

Peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands are widely used in patients with insulin resistance and diabetes. Because coronary artery disease is a major complication for such patients, it is important to determine the effects of PPARgamma activation on arteriosclerosis. Long-term inhibition of endothelial NO synthesis by administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) to rats induces coronary vascular inflammation (monocyte infiltration, monocyte chemoattractant protein-1 [MCP-1] expression) and subsequent arteriosclerosis. We examined the effects of pioglitazone (a PPARgamma ligand) in this rat model to determine whether PPARgamma activation with pioglitazone inhibits arteriosclerosis by its indirect effects on metabolic conditions or by direct effects on the cells participating to the pathogenesis of arteriosclerosis. We found that pioglitazone did not affect metabolic states, systolic blood pressure, or serum NO levels, but did prevent the L-NAME-induced coronary inflammation and arteriosclerosis. Pioglitazone did not reduce local expression of MCP-1 but markedly attenuated increased expression of the MCP-1 receptor C-C chemokine receptor 2 (CCR2) in lesional and circulating monocytes. PPARgamma activation with pioglitazone prevented coronary arteriosclerosis, possibly by its antiinflammatory effects (downregulation of CCR2 in circulating monocytes). Inhibition of the CCR2-mediated inflammation may represent novel antiinflammatory actions of pioglitazone beyond improvement of metabolic state.

Topics: Animals; Anti-Inflammatory Agents; Arteriosclerosis; Blood Glucose; Blood Pressure; Chemokine CCL2; Coronary Artery Disease; Disease Models, Animal; Drug Evaluation, Preclinical; Inflammation; Insulin; Lipids; Male; Monocytes; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Peptidyl-Dipeptidase A; Pioglitazone; Rats; Rats, Inbred WKY; Receptors, CCR2; Receptors, Chemokine; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Thiazoles; Thiazolidinediones; Transcription Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Treatment Outcome

It is thought that transforming growth factor-beta1 (TGF-beta1) might be a key inhibitor of atherogenesis in non-uremic patients. We evaluated the intra- and post-dialytic serum levels of TGF-beta1 in uremic patients to assess if TGF-beta1 is an independent risk factor for cardiovascular diseases, and if any correlation exists between TGF-beta1 and any yet known atherosclerotic risk factors.. We studied 155 patients who were on regular hemodialysis, with or without clinically significant atherosclerotic vascular disease. Forty-one apparently healthy people were enrolled as a control group. TGF-beta1 was evaluated during the midweek dialysis session, at times 0, 30, and 120 minues, at the end of the session, and 3 hours after the session's end. All hitherto known atherosclerotic risk factors also were evaluated. The investigation was performed over a 24-month follow-up.. TGF-beta1 values (mean +/- SD) in dialysis patients were 26.64 +/- 7.0 ng/mL (N=155) compared with 42.31 +/- 6.0 ng/mL in the control group (N=41, P < 0.0001). A weak inverse correlation emerged between TGF-beta1 and age (r=-0.28), TGF-beta1 and lipoprotein(a) [Lp(a); r=-0.35], TGF-beta1 and C-reactive protein (CRP; r=-0.27), and TGF-beta1 and plasminogen activator inhibitor-1 (PAI-1; r=-0.41). TGF-beta1 also correlated with albumin (r=0.31). In the coronary heart disease (CHD) group (N=32) the TGF-beta1 was 26.2 +/- 4.9 ng/mL; in the cerebrovascular disease (CVD) group (N=8) it was 26.7 +/- 3.7 ng/mL and in the peripheral vascular disease (PVD) group (N=9) it was 25.4 +/- 1.7 ng/mL. In dialysis patients with no cardiovascular disease (N=80) TGF-beta1 was 35.1 +/- 6.8 ng/mL (P < 0.0001 vs. CHD, CVD and PVD patients). TGF-beta1 was significantly lower among those patients with triple coronary vessel disease than with the other CHD patients. The Cox analysis demonstrated that a 1 ng/mL reduction in TGF-beta1 concentration was associated with a 9% increase in the relative risk of a cardiovascular event.. TGF-beta1 was significantly reduced in hemodialysis patients, in particular in those with severe cardiovascular disease. Baseline TGF-beta1, diabetes mellitus and serum albumin levels proved to be the only independent contributors to atherosclerotic risk in dialysis patients.

Topics: Adult; Aged; Aged, 80 and over; Coronary Artery Disease; Female; Follow-Up Studies; Genotype; Humans; Kidney Failure, Chronic; Logistic Models; Male; Middle Aged; Myocardial Ischemia; Predictive Value of Tests; Renal Dialysis; Risk Factors; Survival Analysis; Transforming Growth Factor beta; Transforming Growth Factor beta1; Uremia

Accelerated coronary arteriosclerosis remains a major problem for the long-term survival of cardiac transplant recipients. However, the pathogenesis of graft vasculopathy is poorly understood and there is no effective therapy. Tranilast is a promising drug that may prevent post-angioplasty restenosis. Here, we investigated whether orally administered tranilast inhibits the development of intima hyperplasia in a mouse model of cardiac transplantation. Cardiac allografts from BALB/c mice were transplanted heterotopically into C3H/He mice. Mice were administered either vehicle or tranilast everyday by gavage. Morphometrical analysis of the cardiac allografts harvested at 2 months revealed that the administration of tranilast significantly reduced the development of coronary atherosclerosis. In the mice treated with tranilast, up-regulation of the cyclin-dependent kinase inhibitor p21 was observed in the allografts, accompanied by a reduced number of proliferating cells. Tranilast also suppressed transforming growth factor-beta (TGF-beta) expression. Tranilast may be effective in preventing transplant-associated arteriosclerosis through its anti-inflammatory and anti-proliferative effects.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Division; Coronary Artery Disease; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Heart Transplantation; Hyperplasia; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Muscle, Smooth, Vascular; ortho-Aminobenzoates; Transforming Growth Factor beta

Chronic inhibition of endothelial nitric oxide (NO) synthesis by the administration of N:(omega)-nitro-L-arginine methyl ester (L-NAME) to rats induces early vascular inflammatory changes (monocyte infiltration into coronary vessels and monocyte chemoattractant protein-1 [MCP-1] expression) as well as subsequent arteriosclerosis (medial thickening and perivascular fibrosis) and cardiac fibrosis. However, the role of MCP-1 in this process is not known.. We investigated the effect of a specific monoclonal anti-MCP-1 neutralizing antibody in rats treated with L-NAME to determine the role of monocytes in the regulation of cardiovascular remodeling. We found increased expression of MCP-1 mRNA in vascular endothelial cells and monocytes in inflammatory lesions. Cotreatment with an anti-MCP-1 antibody, but not with control IgG, prevented the L-NAME-induced early inflammation and reduced late coronary vascular medial thickening. In contrast, the anti-MCP-1 antibody did not decrease the development of perivascular fibrosis, the expression of transforming growth factor (TGF)-beta(1) mRNA, or systolic pressure overload induced by L-NAME administration.. These results suggest that MCP-1 is necessary for the development of medial thickening as well as monocyte recruitment. In contrast, the pathogenesis of fibrosis may involve other factors, such as TGF-beta(1).

Topics: Animals; Antibodies, Monoclonal; Blood Pressure; Cell Division; Chemokine CCL2; Chronic Disease; Collagen; Coronary Artery Disease; Dermis; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrosis; Inflammation; Male; Monocytes; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Rats; Rats, Inbred WKY; Recombinant Proteins; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Remodeling

Endoglin is a homodimeric membrane glycoprotein primarily expressed on endothelial cells. In association with transforming growth factor (TGF)-ss receptors I and II, it can bind TGF-beta1 and -beta3 and form a functional receptor complex. There is increasing evidence that endoglin can modulate the cellular response to TGF-beta, a factor implicated in vascular lesion formation in human and experimental models. The purpose of this study was to analyze the expression of endoglin in normal and balloon-injured porcine coronary arteries and in normal and atherosclerotic human coronary arteries and to determine its ability to mediate the effects of TGF-beta on the migration of vascular smooth muscle cells (SMCs). In normal porcine coronary arteries, endoglin was of low abundance and was found primarily on endothelial cells and adventitial fibroblasts, as well as on a minority of medial SMCs. On days 3, 7, and 14 after angioplasty, endoglin was present not only on endothelial cells but also on adventitial myofibroblasts and medial SMCs of porcine coronary arteries. By day 28, few or no cells expressed endoglin. In situ hybridization revealed that endoglin mRNA expression appeared to be highest in endothelial cells on days 3, 7, and 14 days after injury and absent thereafter. With a second balloon injury, a similar pattern of endoglin protein and mRNA expression was observed. In human vascular tissue, endoglin immunolabeling was higher in endarterectomy specimens removed from diseased coronary arteries than in normal internal mammary arteries. In vitro, antisense oligonucleotides to endoglin decreased its expression and antagonized the TGF-beta-mediated inhibition of human and porcine SMC migration. In summary, upregulation of endoglin occurs during arterial repair and in established atherosclerotic plaques and may be required for modulation of SMC migration by TGF-beta.

Topics: Angioplasty, Balloon, Coronary; Animals; Antigens, CD; Cell Movement; Cells, Cultured; Coronary Artery Disease; Coronary Vessels; Endarterectomy; Endoglin; Endothelium, Vascular; ErbB Receptors; Flow Cytometry; Gene Expression Regulation; Humans; Immunohistochemistry; In Situ Hybridization; In Vitro Techniques; Muscle, Smooth, Vascular; Oligonucleotides, Antisense; Receptors, Cell Surface; Receptors, Transforming Growth Factor beta; RNA; Swine; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Vascular Cell Adhesion Molecule-1

Plasma concentration of markers of inflammation are increased in patients with atherosclerosis. However, it is unclear whether the pattern and magnitude of this increase vary with the site and extent of disease. In 147 patients undergoing semiquantitative coronary angiography, we measured the acute-phase reactants C-reactive protein (CRP) or serum amyloid A (SAA); the proinflammatory cytokine interleukin 6 (IL-6); the active and total fractions of the anti-inflammatory cytokine transforming growth factor-beta (TGF-beta); the macrophage activation marker neopterin; and the infection marker procalcitonin. Compared with 62 patients without either coronary artery disease (CAD) or peripheral artery disease (PAD), 57 patients with CAD but no PAD showed greater median CRP (0. 4 versus 0.2 mg/dL, P=0.004) and IL-6 (3.8 versus 1.6 pg/mL, P=0. 007) levels and a lower level of active-TGF-beta (57 versus 100 ng/mL, P=0.038). Moreover, CRP, IL-6, and neopterin levels showed a positive and the active TGF-beta level a negative correlation with the extent of coronary atherosclerosis. Compared with these 57 patients with CAD alone, 15 patients with PAD and CAD had higher median levels of SAA (17 versus 7 mg/mL, P=0.008), IL-6 (12 versus 4 pg/mL, P=0.002), neopterin (14 versus 11 mg/dL, P=0.006), and total TGF-beta (11834 versus 6417 ng/L, P=0.001). However, these strong univariate associations of markers of inflammation and atherosclerosis were lost in multivariate analysis once age, sex, and high density lipoprotein cholesterol or fibrinogen were taken into account. Increased plasma levels of CRP, SAA, IL-6, TGF-beta, neopterin, and procalcitonin constitute an inflammatory signature of advanced atherosclerosis and are correlated with the extent of disease but do not provide discriminatory diagnostic power over and above established risk factors.

Topics: Acute-Phase Reaction; Adult; Aged; Arteritis; Biomarkers; Blood Glucose; Cholesterol, HDL; Cholesterol, LDL; Constriction, Pathologic; Coronary Artery Disease; Female; Fibrinogen; Homocysteine; Humans; Interleukin-6; Intermittent Claudication; Logistic Models; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Popliteal Artery; Risk Assessment; Transforming Growth Factor beta; Triglycerides

Topics: Chromosome Mapping; Coronary Angiography; Coronary Artery Disease; Coronary Disease; Female; Genetic Predisposition to Disease; Humans; Male; Myocardial Infarction; Phenotype; Risk Factors; Transforming Growth Factor beta

Immunohistochemical and morphometrical studies were performed to elucidate the specificity of atherosclerosis in the descending branch (the segments 5 and 6) of the left coronary artery associated with acute myocardial infarction (AMI) in the anterior wall of the heart and non-insulin-dependent diabetes mellitus (NIDDM). The NIDDM without AMI group showed diffuse intimal thickening with smooth muscle cells, combined with much more intense immunostaining of tenascin than the non diabetic groups. The AMI without NIDDM group showed atheromatous thickening with decreased smooth muscle cells, a large number of macrophage and TUNEL-positive cells compared with the groups without AMI. However, the AMI with NIDDM group revealed atherosclerotic lesion with decreased smooth muscle cells, increased macrophages and TUNEL positive cells associated with the increased localization of tenascin and TGF-beta1 compared with the control. These findings suggest that the specificity of coronary atherosclerosis in diabetic patients may be the extensive atherosclerotic changes associated with increased tenascin. In AMI with NIDDM, increased TGF beta1 may induce apoptosis in the atheroma and coronary dysfunction, contributing to the development of acute myocardial infarction.

Topics: Actins; Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Case-Control Studies; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; DNA Fragmentation; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Macrophages; Middle Aged; Muscle, Smooth, Vascular; Myocardial Infarction; Tenascin; Transforming Growth Factor beta

Recent evidence has led us to propose that transforming growth factor-beta (TGF-beta) is a key inhibitor of atherosclerosis. We show here that a population of patients with advanced atherosclerosis all have less active TGF-beta in their sera than patients with normal coronary arteries, with a fivefold difference in average concentration between the two groups. This correlation with atherosclerosis is much stronger than for other known major risk factors and it may therefore have important diagnostic and prognostic significance. Aspirin medication correlates with an increase in active TGF-beta concentration, indicating that therapeutic interventions for TGF-beta are possible.

Topics: Aged; Aspirin; Cholesterol, LDL; Coronary Artery Disease; Female; Humans; Male; Middle Aged; Risk Factors; Transforming Growth Factor beta