transforming-growth-factor-beta and Coronary-Disease

Revascularization surgeries such as coronary artery bypass grafting (CABG) are sometimes necessary to manage coronary heart disease (CHD). However, more than half of these surgeries fail within 10 years due to the development of intimal hyperplasia (IH) among others. The cytokine transforming growth factor-beta (TGFß) and its signaling components have been found to be upregulated in diseased or injured vessels, and to promote IH after grafting. Interventions that globally inhibit TGFß in CABG have yielded contrasting outcomes in

Topics: Activin Receptors, Type II; Coronary Artery Bypass; Coronary Disease; Graft Occlusion, Vascular; Humans; Hyperplasia; Myocytes, Smooth Muscle; Receptor, Transforming Growth Factor-beta Type I; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta

Hypertension is prevalent world-wide, and it affects over 50 million individuals in the United States alone. African Americans (blacks) have a high prevalence of hypertension, develop it at an earlier age, and suffer excessively from severe or malignant hypertension. They also have a high prevalence of target organ damage attributable to hypertension, including left ventricular hypertrophy, stroke, end-stage renal disease (ESRD) and coronary artery disease. Hypertensive nephrosclerosis is particularly more prevalent in blacks compared to whites, and there is evidence that factors in addition to elevated blood pressure contribute to its pathogenesis. Transforming growth factor-beta 1 (TGF-beta1) is a fibrogenic cytokine that has been implicated in the development and progression of experimental and human renal diseases. We have demonstrated that blacks with ESRD have higher circulating levels of TGF-beta1 protein compared to whites with ESRD. We have also found that hyperexpression of TGF-beta1 is more frequent in blacks with hypertension than in whites. We propose that TGF-beta1 hyperexpression may be an important mediator of hypertension and hypertensive nephrosclerosis. We hypothesize also that the increased frequency of TGF-beta1 hyperexpression may contribute to the excess burden of ESRD in blacks. Based on our hypotheses, and the observations that angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists reduce angiotensin II-mediated stimulation of TGF-beta1 production, we propose that treatment with these agents might be efficacious in preventing or slowing the progression of target organ damage in hypertensive blacks.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Black People; Coronary Disease; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Linear Models; Prevalence; Stroke; Transforming Growth Factor beta; White People

Since the original report of Kawasaki disease in 1967 more than 150,000 cases have been reported in Japan. Although there have been no nationwide epidemics in Japan since 1987, more than 6,000 newly diagnosed cases are reported every year, and the number has been increasing year by year despite the decreasing birth rate. The etiology of the disease is still unknown. High dose intravenous gammaglobulin is currently used during the acute phase in 84% of the patients in Japan with a concomitant decrease in coronary arterial sequelae. However, 7-13% of the patients still have persistent coronary artery aneurysms after the acute stage. The aneurysms are seen mostly in the proximal coronary arteries, and are often associated with aneurysms in the distal coronary artery segments (Figure 1A, 2A). Most of the patients show a decrease in the size of aneurysms soon after the acute phase (Figure 1B). However, the aneurysms may progress to obstructive lesions even after initial regression (Figures 1C, D, 2B). Such obstructive lesions may cause sudden death or myocardial infarction. Long term follow-up of coronary artery lesions has revealed several characteristic features, including progressive localized stenosis (Figure 1D), extensive recanalizations (Figure 2D) and development of collateral arteries. Progressive increases in aneurysm size and the appearance of new aneurysms in the late phase have also been reported. The basic mechanisms of the coronary arterial remodeling in Kawasaki disease have not yet been elucidated. Only recently has immunohistochemical staining in formalin-fixed specimens become feasible. This is a major technical breakthrough since it is almost impossible to obtain fresh frozen specimens of coronary artery lesions of Kawasaki discase. In this paper, we compare immunohistochemical findings in coronary artery lesions with the corresponding coronary angiographic findings, and attempt to make inferences as to the mechanism of remodeling both in early and late phases of the disease based on the expression of vascular growth factors.

Topics: Adolescent; Child; Coronary Aneurysm; Coronary Angiography; Coronary Disease; Coronary Vessels; Endothelial Growth Factors; Fibroblast Growth Factor 2; Humans; Immunohistochemistry; Lymphokines; Mucocutaneous Lymph Node Syndrome; Myocardial Infarction; Platelet-Derived Growth Factor; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Arteriosclerosis; Carotid Artery Diseases; Coronary Disease; Endothelium, Vascular; Fibrin; Humans; In Vitro Techniques; Lipoprotein(a); Monocyte Chemoattractant Proteins; Risk Factors; Transforming Growth Factor beta

Soybeans contain estrogenic isoflavones that may influence plasma concentrations of transforming growth factor beta(1) (TGF-beta(1)) and plasma lipid and hemostatic risk factors for coronary heart disease.. We compared the effects of moderate intakes of soy protein containing intact phytoestrogens (high-isoflavone diet) and soy protein from which most of the phytoestrogens had been extracted (low-isoflavone diet) on active TGF-beta(1) concentrations and plasma lipid and hemostatic risk factors for coronary heart disease.. A randomized crossover trial was conducted in 22 young, healthy, normolipidemic subjects (5 men and 17 women) who consumed diets providing 56 or 2 mg isoflavones/d for 17 d each with a 25-d washout period between treatments. Fasting blood samples were obtained on days 13 and 14 of each treatment to measure plasma isoflavone, lipid, fibrinogen, and active TGF-beta(1) concentrations and factor VII coagulant and plasminogen activator inhibitor type 1 activities.. Plasma isoflavone concentrations were 100-999 times greater after the high-isoflavone diet than after the low-isoflavone diet (P < 0.05). Plasma HDL-cholesterol and apolipoprotein A-I concentrations were 4% (95% CI: 1%, 8%) and 6% (95% CI: 3%, 10%) higher, respectively, after the high-isoflavone diet than after the low-isoflavone diet (P < 0.01 for both).. Compared with soy protein from which most of the phytoestrogens have been extracted, soy protein with intact phytoestrogens increases HDL-cholesterol and apolipoprotein A-I concentrations but does not influence LDL-cholesterol, TGF-beta(1), or fibrinogen concentrations; factor VII coagulant activity; or plasminogen activator inhibitor type 1 activity in normolipidemic, healthy subjects.

Topics: Adult; Cholesterol, HDL; Coronary Disease; Cross-Over Studies; Female; Humans; Isoflavones; Male; Risk Factors; Soybean Proteins; Transforming Growth Factor beta; Transforming Growth Factor beta1

Hormone replacement therapy (HRT) in postmenopausal women may reduce the cardiovascular risk. A dominant protective role of transforming growth factor beta (TGF-beta1) on coronary arteries has been proposed. Lp(a) lipoprotein may block the activation of latent TGF-beta1. Given this background, we examined the effects of HRT on TGF-beta1 and Lp(a) lipoprotein in 99 postmenopausal women. The women had angiographically documented coronary heart disease (CHD) and were randomized to either sequential transdermal 17beta-oestradiol for 14 weeks and then medroxyprogesterone (MPA) for 14 days (HRT) or to a control group (C).. Serum levels of TGF-beta1 were increased in the HRT group compared with the C group after 3 months' treatment and this effect was sustained after 12 months. There was a significant reduction in Lp(a) lipoprotein serum levels after 3 months' treatment in the HRT group compared with the C group. However, after 12 months, no significant difference in changes in Lp(a) lipoprotein serum levels was detected between the two groups.. The novel observation that transdermal 17beta-oestradiol in postmenopausal women increases levels of TGF-beta1 and lowers the concentration of Lp(a) lipoprotein suggests yet another possible mechanism for the cardioprotective effect of HRT. Whereas combination therapy of oestradiol and MPA preserves the beneficial effect on TGF-beta1, it reduces the unopposed oestradiol effects on Lp(a) lipoprotein.

Topics: Administration, Cutaneous; Aged; Coronary Disease; Estradiol; Female; Hormone Replacement Therapy; Humans; Lipoprotein(a); Medroxyprogesterone; Middle Aged; Postmenopause; Progesterone Congeners; Radiography; Risk Factors; Transforming Growth Factor beta; Treatment Outcome

We have quantified levels of CD105, its ligand TGFbeta and receptor-ligand complexes in sera from healthy individuals (n=31), patients with triple vessel disease documented by coronary angiography (TVD; n=36) and patients with chest pain and a positive exercise electrocardiogram but with normal coronary angiogram (NCA; n=30). Both active TGFbeta1 and active plus acid-activatable TGFbeta1 [(a+l)TGFbeta1] were significantly depressed in patients with TVD compared with the other two groups (P

Topics: Aged; Angina Pectoris; Antigen-Antibody Complex; Antigens, CD; Biomarkers; Coronary Angiography; Coronary Disease; Electrocardiography; Endoglin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Probability; Prognosis; Radioimmunoassay; Receptors, Cell Surface; Reference Values; Sensitivity and Specificity; Signal Transduction; Statistics, Nonparametric; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1

Histone deacetylase (HDAC) determines the acetylation status of histones, thereby regulating gene expression. HDAC inhibitors have been demonstrated to suppress cardiomyocyte growth in vitro and in vivo. We assessed here whether HDAC1 exerts an aggravating effect on coronary heart disease (CHD). Epigenetic probe array revealed that HDAC1 was overexpressed in patients with CHD. HDAC1 was then downregulated in rat cardiomyocytes, and microRNA microarray analysis was performed to detect downstream targets of HDAC1, followed by chromatin immunoprecipitation validation. HDAC1 inhibited miR-182 expression through deacetylation. miR-182 was poorly expressed in patients with CHD. Using enzyme-linked immunosorbent assay, Reverse transcription-quantitative PCR, hematoxylin-eosin staining, terminal deoxynucleotidyl transferase (TdT)-mediated 2'-deoxyuridine 5'-triphosphate (dUTP) nick-end labeling assay, and immunohistochemistry, we observed that HDAC1 downregulation promoted cardiac function, restored lipid levels, reduced myocardial injury markers and inflammatory factors, and alleviated myocardial tissue damage and apoptosis in CHD rats. By contrast, miR-182 downregulation exacerbated injury in rats in the presence of HDAC1 knockdown. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the target genes of miR-182 were mainly enriched in the transforming growth factor (TGF)-β/Smad pathway. Western blot also validated that HDAC1/miR-182 modulated the TGF-β/Smad pathway activity. Our results demonstrated that HDAC1 repressed miR-182 and activated the TGF-β/Smad pathway to promote CHD.

Topics: Animals; Apoptosis; Coronary Disease; Histone Deacetylase 1; Humans; MicroRNAs; Rats; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

The mechanism whereby the 9p21.3 locus confers risk for coronary artery disease remains incompletely understood. Risk alleles are associated with reduced expression of the cell cycle suppressor genes CDKN2A (p16 and p14) and CDKN2B (p15) and increased vascular smooth muscle cell proliferation. We asked whether risk alleles disrupt transcription factor binding to account for this effect.. A bioinformatic screen was used to predict which of 59 single nucleotide polymorphisms at the 9p21.3 locus disrupt (or create) transcription factor binding sites. Electrophoretic mobility shift and luciferase reporter assays examined the binding and functionality of the predicted regulatory sequences. Primary human aortic smooth muscle cells (HAoSMCs) were genotyped for 9p21.3, and HAoSMCs homozygous for the risk allele showed reduced p15 and p16 levels and increased proliferation. rs10811656 and rs4977757 disrupted functional TEF-1 TEC1 AbaA domain (TEAD) transcription factor binding sites. TEAD3 and TEAD4 overexpression induced p16 in HAoSMCs homozygous for the nonrisk allele, but not for the risk allele. Transforming growth factor β, known to activate p16 and also to interact with TEAD factors, failed to induce p16 or to inhibit proliferation of HAoSMCs homozygous for the risk allele. Knockdown of TEAD3 blocked transforming growth factor β-induced p16 mRNA and protein expression, and dual knockdown of TEAD3 and TEAD4 markedly reduced p16 expression in heterozygous HAoSMCs.. Here, we identify a novel mechanism whereby sequences at the 9p21.3 risk locus disrupt TEAD factor binding and TEAD3-dependent transforming growth factor β induction of p16 in HAoSMCs. This mechanism accounts, in part, for the 9p21.3 coronary artery disease risk.

Topics: Adolescent; Adult; Alleles; Aorta; Cells, Cultured; Chromosomes, Human, Pair 9; Coronary Disease; Cyclin-Dependent Kinase Inhibitor p16; DNA-Binding Proteins; Female; Gene Knockdown Techniques; Genes, p16; Genes, Reporter; Humans; Male; Middle Aged; Muscle Proteins; Muscle, Smooth, Vascular; Polymorphism, Single Nucleotide; Recombinant Proteins; TEA Domain Transcription Factors; Transcription Factors; Transforming Growth Factor beta; Young Adult

Topics: Chromosomes, Human, Pair 9; Coronary Disease; Cyclin-Dependent Kinase Inhibitor p16; DNA-Binding Proteins; Female; Humans; Male; Muscle Proteins; Polymorphism, Single Nucleotide; Transcription Factors; Transforming Growth Factor beta

Impairment of coronary flow reserve (CFR) has been generally demonstrated in diabetic patients and animals with microvascular complications but without obvious obstructive coronary atherosclerosis. There have been few studies investigating CFR in cases of relatively well-controlled therapy. The purpose of this study is to evaluate the effect of treatment with a Sphingosine-1-phosphate (S1P) receptor potent agonist, FTY720, on early diabetic rats in terms of CFR. METHODS AND RESULTS: Male Sprague-Dawley (SD) rats were divided into 3 groups: (1) streptozotocin-uninjected rats (control rats); (2) streptozotocin-injected hyperglycemic rats (diabetic group); and (3) FTY720-fed and streptozotocin-injected hyperglycemic rats. FTY720 (1.25 mg/kg per day orally) was administrated for 9 weeks in SD rats (from 6 weeks old to 15 weeks old). CFR was evaluated by (13)NH3-positron emission tomography. No obvious pathological changes of macrovascular atherosclerosis were observed in each group. Diabetic rats had impaired CFR compared with the control group (1.39±0.26 vs. 1.94±0.24, P<0.05). Treatment with FTY720 for 9 weeks attenuated the heart histological changes and improved CFR in 32% of diabetic rats (1.84±0.36 vs. 1.39±0.26, P<0.05).. In summary, long-term therapy with the Sphingosine-1-phosphate receptor agonist, FTY720, improved CFR by attenuating the heart histological changes, and it might have a beneficial effect on coronary microvascular function in diabetic rats.

Topics: Ammonia; Animals; Blood Glucose; Capillaries; Cell Adhesion Molecules; Collagen; Coronary Circulation; Coronary Disease; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Drug Evaluation, Preclinical; Fingolimod Hydrochloride; Gene Expression Regulation; Interleukin-6; Lysophospholipids; Male; Microcirculation; Myocardium; Nitrogen Radioisotopes; Positron-Emission Tomography; Propylene Glycols; Rats; Rats, Sprague-Dawley; Receptors, Lysosphingolipid; Sphingosine; Transforming Growth Factor beta

The aim of this study was to assess the influence of IL-10 and TGFbeta1 gene polymorphisms on the development of acute rejection and coronary disease in pediatric heart transplant recipients.. Patients were classified as either Rejectors or Nonrejectors. Coronary artery disease (CAD) was diagnosed by angiography or on macroscopic examination. Genotyping PCR-SSP were performed for IL-10 and TGFbeta1 (codon 10 and 25) in 111 patients. Thirty-nine were Rejectors and 31 developed CAD.. The proportion of IL-10 low-producers was higher in Rejectors than in Nonrejectors (respectively 46% versus 22%, P=0.009). IL-10 gene polymorphism was not associated with CAD. TGFbeta1-codon10-25 high-producers were 92.3% in Rejectors and 75% in Nonrejectors (P=0.026), 93.5% in patients with CAD and 76.2% in patients free from CAD (P=0.037). TGFbeta1-codon25 high-production separately analyzed correlated with CAD (31/31 high-producers in CAD=100% versus 69/80 in noCAD patients=86.2%, P=0.03). TGFbeta1-codon10 gene polymorphisms were not associated with CAD.. IL-10 low-producers have an increased risk of acute rejection. High-expressors of TGFbeta1-codon10-25 have an increased risk of acute rejection and CAD, while TGFbeta1-codon25 high-production is associated with coronary disease. Genetic polymorphism may reveal patients at high-risk in whom therapies and monitoring should be adjusted.

Topics: Adolescent; Child; Child, Preschool; Coronary Disease; Female; Graft Rejection; Heart Transplantation; Humans; Male; Polymorphism, Genetic; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transplantation, Homologous

The role of cytokine gene polymorphism and its association with acute heart allograft rejection and cardiac allograft vasculopathy (CAV) is controversial. The role of growth factor gene polymorphism has never been investigated in heart allograft recipients.. Seventy heart transplant recipients were studied. Mean age at transplant was 50.4 +/- 12.4 years (73% white, 91% male). Patients were followed for an average of 28 +/- 12 months. Cellular rejection episodes were determined based on criteria established by the International Society of Heart and Lung Transplantation. Angiography and intravascular ultrasound (IVUS) were performed annually. Cytokine and growth factor polymorphism data were analyzed using the single-nucleotide polymorphism polymerase chain reaction (SNP PCR) approach.. Patients who developed early CAV, documented by angiography, had increased frequency of the interferon-gamma high-producer phenotype, increased frequency of PDGF-286 AA, and decreased frequency of PDGF-1135 CC (p < 0.03, p < 0.03 and p = 0.01, respectively). Platelet-derived growth factor (PDGF) associations with early CAV were substantiated when vasculopathy was determined by IVUS. Additional associations were identified with vascular endothelial growth factor (VEGF) polymorphisms-1154 GG and -2578 AC (p < 0.03 and p = 0.01, respectively). Some of these associations translated to decreased patient survival, as indicated by Kaplan-Meier analysis. No significant association was identified between cytokine gene polymorphism (tumor necrosis factor-alpha, transforming growth factor-beta, interferon-gamma, interleukin-6 and interleukin-10) and acute cellular rejection episodes.. These data suggest an association between PDGF and VEGF polymorphism and CAV. It is essential, however, due to the redundancy of the immune system and other confounding factors, that future studies be centrally conducted and include multiple programs, large cohorts of patients and properly chosen controls. Only then will we be able to identify the true association between cytokine and growth factor polymorphism and heart transplant outcome.

Topics: Aged; Coronary Angiography; Coronary Disease; Female; Heart Transplantation; Host vs Graft Reaction; Humans; Interferon-gamma; Interleukin-10; Interleukin-6; Male; Middle Aged; Phenotype; Platelet-Derived Growth Factor; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins c-sis; Transforming Growth Factor beta; Transplantation, Homologous; Tumor Necrosis Factor-alpha; Ultrasonography, Interventional; Vascular Endothelial Growth Factor A

We have observed increased levels of transforming growth factor-beta1 (TGF-beta1) in human hibernating myocardium (HM). Impaired ventricular function in HM is known to be restored to normal following revascularization implying that myocardial structure in HM is to a certain degree preserved. We have therefore tested whether TGF-beta1 can imitate features of HM by reducing the number and frequency of beating cells (chronotropism) and structural remodeling of cultured adult rat cardiomyocytes (ARC), thus saving substrate, energy, and oxygen. Parameters measured were cell size, protein synthesis, protein degradation, protein content, myofibrillogenesis, and chronotropism. ARC were stimulated for 6 days with sera from patients with coronary heart disease, as this period led to a maximum response of cells. An increase of 90% in cell surface area following such treatment was reduced to a 20% increase of the original size by TGF-beta1. Concomitantly, the rate of protein synthesis dropped from 3.6-fold to 2.4-fold, and myofibrillogenesis was reduced. TGF-beta1 downregulated both the number of contracting cells from 81% to 10% and the frequency from 52 to nine beats per minute. However, TGF-beta1 treatment did not reduce the augmentation of protein content (1.28-fold versus 1.25-fold) indicating that protein degradation was also inhibited. Similar results were obtained with serum from healthy volunteers. The effects of TGF-beta1 were reversible. We conclude that TGF-beta1 constrains protein turnover and beating activity in underperfused myocardium, thus mediating protection by adapting myocytes to shortages in blood supply.

Topics: Animals; Cell Culture Techniques; Cell Enlargement; Cell Size; Cells, Cultured; Coronary Disease; Culture Media; Culture Media, Serum-Free; Down-Regulation; Female; Heart Ventricles; Humans; Immunohistochemistry; Male; Microscopy, Interference; Middle Aged; Myocardial Contraction; Myocytes, Cardiac; Rats; Rats, Wistar; Serum; Transforming Growth Factor beta; Transforming Growth Factor beta1

Vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-beta1) play an important role in angiogenesis. We wanted to determine if concentrations of growth factors in the coronary sinus (CS) and right atrium (RA) are higher in coronary artery disease patients with total occlusions than in those with partial occlusions. Fifty-one patients scheduled for coronary artery angiography were evaluated for possible recruitment. A 6F Goodale-Lubin catheter was used to collect blood from the CS and RA. Data for all but four patients were gathered successfully, leaving 47 study patients. The reviewer was blinded to growth factor data when interpreting coronary angiographic findings. Of the 47 enrolled patients, 32 had at least one diseased vessel, seven of whom had at least one major total epicardial coronary occlusion. In all 32 patients, the concentrations of VEGF in the CS were higher than those in the RA (31.5 +/- 2.7 vs 27.1 +/- 1.8 pg/mL; p = 0.005). Patients with total occlusions had higher VEGF concentrations in the CS than those with non-total occlusions (38.9 +/- 8.0 vs 29.5 +/- 2.6 pg/mL; p = 0.037). The differences in TGF-beta1 in the two groups were not statistically significant. The higher CS VEGF concentrations in patients with total occlusion indicate that VEGF may play a part in the development of angiogenesis.

Topics: Aged; Arterial Occlusive Diseases; Coronary Angiography; Coronary Disease; Coronary Stenosis; Coronary Vessels; Enzyme-Linked Immunosorbent Assay; Female; Heart Atria; Humans; Hypertension; Male; Middle Aged; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Obesity and insulin resistance confer increased risk for accelerated coronary disease and cardiomyopathic phenomena. We have previously shown that inhibition of angiotensin-converting enzyme (ACE) prevents coronary perimicrovascular fibrosis in genetically obese mice that develop insulin resistance. This study was performed to elucidate mechanism(s) implicated and to determine the effects of attenuation of angiotensin II (Ang) II. Genetically obese ob/ob mice were given ACE inhibitor (temocapril) or Ang II type 1 (AT(1)) receptor blocker (olmesartan) from 10 to 20 weeks. Cardiac expressions of plasminogen activator inhibitor (PAI)-1, the major physiologic inhibitor of fibrinolysis, and transforming growth factor (TGF)-beta(1), a prototypic profibrotic molecule, were determined and extent of perivascular coronary fibrosis was measured. Twenty-week-old obese mice exhibited increased plasma levels of PAI-1 and TGF-beta(1) compared with the values in lean counterpart. Perivascular coronary fibrosis in arterioles and small arteries was evident in obese mice that also showed increased left ventricular collagen as measured by hydroxyproline assay. Immunohistochemistry confirmed the deposition of perivascular type 1 collagen. Markedly increased PAI-1 and TGF-beta were seen immunohistochemically in coronary vascular wall and confirmed by western blotting. When obese mice were treated with temocapril or olmesartan from 10 to 20 weeks, both were equally effective and prevented increases in perivascular fibrosis, plasma PAI-1 and TGF-beta(1), left ventricular collagen and mural immunoreactivity for PAI-1, TGF-beta and collagen type 1. The c-Jun NH(2)-terminal kinase (JNK) activity was elevated in the left ventricle of obese mice (western) and blocked by temocapril and olmesartan. Ang II-mediated upregulation of PAI-1 and TGF-beta(1) with collagen deposition may explain the mechanism of perivascular fibrosis in obese mice. ACE inhibition and blockade of AT(1) receptor may prevent coronary perivascular fibrosis and collagen deposition even before development of overt diabetes. JNK activation may be a mediator of obesity-related cardiac dysfunction and a potential therapeutic target.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Collagen Type I; Coronary Disease; Coronary Vessels; Fibrosis; Heart Ventricles; Imidazoles; Insulin; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Male; Matrix Metalloproteinase 9; Mice; Mice, Obese; Obesity; Olmesartan Medoxomil; Phosphorylation; Plasminogen Activator Inhibitor 1; Tetrazoles; Thiazepines; Transforming Growth Factor beta

Despite extensive animal experimental evidence, there are few data on the relation of growth factors and collateral function in humans.. In 104 patients with a chronic total coronary occlusion (CTO; >2 weeks' duration), collateral function was assessed invasively during recanalization by intracoronary Doppler and pressure recordings. A collateral resistance index, R(Coll), was calculated. Blood samples were drawn from the distal coronary bed supplied by the collaterals and from the aortic root to measure basic fibroblast growth factor (bFGF), monocytic chemotactic protein-1 (MCP-1), transforming growth factor-beta (TGF-beta), placenta growth factor (PlGF), and tumor necrosis factor-alpha (TNF-alpha). The bFGF concentration in the collateralized artery was higher than in the aortic root (34+/-20 versus 18+/-14 pg/mL; P<0.001). bFGF was highest in recent occlusions (2 to 12 weeks) with the highest R(Coll). Higher collateral concentrations were also observed for MCP-1, TGF-beta, and PlGF, but without a close relation to the duration of occlusion. TNF-alpha was not increased in collaterals compared with the systemic circulation. MCP-1, PlGF, and TGF-beta were significantly increased in small collaterals with the highest shear stress. Diabetic patients had lower bFGF and higher MCP-1 levels than nondiabetics.. In CTOs, the continuous release of bFGF into collaterals showed a close relation to the duration of occlusion and collateral function, which underscores its therapeutic potential. Other factors influencing growth factor release appeared to be shear stress for MCP-1, TGF-beta, and PlGF and the presence of diabetes.

Topics: Aged; Aorta; Chemokine CCL2; Collateral Circulation; Comorbidity; Coronary Disease; Coronary Vessels; Diabetes Complications; Female; Fibroblast Growth Factor 2; Growth Substances; Hemorheology; Humans; Male; Middle Aged; Organ Specificity; Placenta Growth Factor; Pregnancy Proteins; Stress, Mechanical; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Ultrasonography, Interventional; Vascular Resistance

Transforming growth factor-beta1 (TGF-beta1) is involved in different physiological and pathological processes, including atherogenesis. High plasma lipoprotein(a) (Lp(a)) concentration is an established independent risk factor that may interfere with the plasmin-mediated TGF-beta1 activation. Both Lp(a) and TGF-beta1 are thought to influence the expression of cellular adhesion molecules (CAMs), also involved in the process of atherogenesis. Whereas many studies confirmed the association between high plasma Lp(a) levels and coronary artery disease (CAD), conflicting results were obtained in different studies in which the changes of TGF-beta1 and CAM concentrations in CAD patients were investigated. The aim of this case-control study was to explore the association of circulating TGF-beta1, Lp(a) and CAMs (intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin) levels with the occurrence and severity of angiographically assessed coronary artery disease. Plasma TGF-beta1, Lp(a), ICAM-1, VCAM-1 and E-selectin concentrations were measured in 100 patients with angiographically assessed CAD and 100 healthy blood donors matched according to age and gender. Lp(a) and TGF-beta1 were significantly higher in patients than in healthy controls (p < 0.001 and p < 0.01, respectively), but no significant correlation between the TGF-beta1 and Lp(a) values was found. The CAM concentrations obtained in CAD patients did not differ significantly as compared with the corresponding values in the controls. None of the measured parameters were influenced by the severity of CAD.

Topics: Adult; Aged; Biomarkers; Coronary Angiography; Coronary Disease; E-Selectin; Female; Humans; Intercellular Adhesion Molecule-1; Lipoprotein(a); Male; Middle Aged; Reference Values; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vascular Cell Adhesion Molecule-1

Diabetes and renal failure have been associated with extremely high restenosis rates following successful angioplasty, resulting in increased morbidity and mortality. Advanced glycosylation end products (AGEs) accumulate in vascular tissues with aging and at an accelerated rate in diabetes and renal failure. AGEs are particularly abundant at sites of atherosclerotic lesions. AGEs interact with specific receptors (RAGE) present on all cells relevant to the restenosis process including inflammatory cells and smooth muscle cells. AGEs-RAGE interaction in vessel wall may lead to inflammation, smooth muscle cell proliferation, and extracellular matrix production, culminating in exaggerated intimal hyperplasia and restenosis. Following arterial injury, the interaction of AGEs with monocytes expressing RAGE can promote migration of inflammatory cells into the lesion and subsequent release of growth factors and cytokines. Binding of AGEs-RAGE on smooth muscle cells increases chemotactic migration and cellular proliferation. AGEs trigger the generation of reactive oxygen species, and upregulate the multifunctional transcription factor NF-kappa B. Finally, AGEs can augment extracellular matrix production by upregulating transforming growth factor-beta. Thus, accumulation of AGEs in vessel wall provides a common mechanism for the high restenosis rates of patients with diabetes and renal failure.

Topics: Angioplasty, Balloon, Coronary; Coronary Disease; Coronary Restenosis; Cytokines; Diabetic Angiopathies; Diabetic Nephropathies; Extracellular Matrix; Glycation End Products, Advanced; Growth Substances; Humans; Hyperplasia; Kidney Failure, Chronic; Models, Biological; Muscle, Smooth, Vascular; NF-kappa B; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Stents; Transforming Growth Factor beta; Tunica Intima; Tunica Media

Transforming growth factor beta (TGF-beta1) is involved in a variety of physiological processes as well as in many diseases. Both in vitro and in vivo evidence suggest that TGF-beta1 may influence atherogenesis and a dominant protective role of TGF-beta1 on coronary arteries has been proposed. On the other hand, increased levels of soluble adhesion molecules have been found in patients with atherosclerosis, and adhesion of monocytes to the endothelium followed by migration to the intima, has been proved to be an early event in atherosclerosis. The purpose of the present investigation was to look at a possible relationship between circulating active TGF-beta1 and adhesion molecules in postmenopausal women with angiographically verified coronary heart disease (CHD) (n=118).. Serum levels of the active form of TGF-beta1 showed a tendency to be lower in patients with increasing number of vessels with more than 50% stenosis (P=0.058), and there was higher TGF-beta1 in the group with one vessel disease compared with those with two or more vessels affected (P=0.041). Additionally, negative association between TGF-beta1 and VCAM-1 was found (r=-0.26, P=0.023). However, no associations were observed between TGF-beta1 and intercellular adhesion molecule-1 (ICAM-1) or E-selectin in the present study.. We observed an inverse correlation between the active form of TGF-beta1 and VCAM-1 in postmenopausal women with verified CHD. These results may suggest a role of TGF-beta1 in CHD.

Topics: Coronary Disease; E-Selectin; Female; Humans; Middle Aged; Postmenopause; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1

Recent studies have indicated that a number of factors contribute to the pathophysiology in response to nitric oxide synthase (NOS) inhibition. We previously demonstrated that plasminogen activator inhibitor-1 deficient (PAI-1-/-) mice are protected against hypertension and perivascular fibrosis induced by relatively short-term NOS inhibition. In this study, we compared the temporal changes in systolic blood pressure and coronary perivascular fibrosis induced by long-term treatment with N(omega)-nitro- L -arginine methyl ester (L -NAME) in wild type (WT), PAI-1(-/-) and tissue-type plasminogen activator deficient (t-PA-/-) mice. After initiating L -NAME, systolic blood pressure increased in all groups at 2 weeks. Over a 16 week study period, systolic blood pressure increased to 143+/-3 mmHg (mean+/-SEM) in WT animals, 139+/-2 in t-PA-/- mice vs 129+/-2 in PAI-1-/- mice (P < 0.01). Coronary perivascular fibrosis increased in L -NAME-treated WT and t-PA(-/-) mice compared to each control group (P<0.01 in WT, P<0.05 in t-PA-/-), while PAI-1-/- mice were protected against fibrosis induced by L -NAME. t-PA deficiency did not accentuate the vascular pathology or the changes in blood pressure. In situ zymography demonstrated augmented gelatinolytic activity in PAI-1-/- mice at baseline, suggesting that PAI-1 deficiency prevents the increase of collagen deposition by promoting matrix degradation. Plasma TGF-beta1 levels increased in L -NAME-treated WT and PAI-1-/- mice (P < 0.01), but not in L -NAME-treated t-PA-/- mice. These findings support the hypothesis that the plasminogen activator system protects against the structural vascular changes induced by long-term NOS inhibition. While PAI-1 deficiency protects against L -NAME-induced hypertension and perivascular fibrosis, t-PA deficiency does not exacerbate the vascular pathology or hypertension.

Topics: Animals; Body Weight; Coronary Disease; Coronary Vessels; Enzyme Inhibitors; Fibrosis; Hemodynamics; Hypertension; Mice; Mice, Inbred C57BL; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Plasminogen Activators; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta

Inflammatory cytokines play an important role in mediating inflammatory/proliferative responses including atherosclerosis. However, their role in the pathogenesis of restenosis after percutaneous transluminal coronary angioplasty (PTCA) remains to be clarified.. To determine plasma levels of inflammatory cytokines as well as cytokine-generation capacities of monocytes before PTCA and after the follow-up period.. Plasma levels of cytokines in 34 consecutive patients before and 3-6 months after PTCA were measured by enzyme-linked immunosorbent assay. We measured the plasma levels of macrophage-colony-stimulating factor (MCSF) and transforming growth factor-beta. Cytokine-generation capacities of monocytes were also measured by a whole-blood induction method with lipopolysaccharide. The levels of cytokines measured for assessment of the capacities included those of interleukin-1alpha, interleukin-1beta, interleukin-6, granulocyte-colony-stimulating factor, tumor necrosis factor-alpha and interferon-gamma.. Plasma levels of MCSF in patients without restenosis (n = 20) decreased significantly (from 1460+/-138 microg/ml before PTCA to 1039+/-125 microg/ml after the follow-up period, P < 0.01), whereas those in patients with restenosis (n = 14) increased significantly (from 1107+/-105 microg/ml before PTCA to 1039+/-125 microg/ml after the follow-up period, P < 0.05). We noted a positive correlation between the increase in plasma levels of MCSF and the extent of loss of lumen by restenosis. Cytokine-generation capacities of monocytes for interleukin-1alpha and interleukin-1beta of patients with restenosis significantly increased but those of patients without restenosis did not. Furthermore, plasma levels of C-reactive protein decreased significantly only in patients without restenosis after the follow-up period.. These results suggest that inflammatory changes mediated by cytokines may be involved in the pathogenesis of restenosis after PTCA.

Topics: Aged; Angioplasty, Balloon, Coronary; C-Reactive Protein; Coronary Disease; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Macrophage Colony-Stimulating Factor; Male; Monocytes; Recurrence; Time Factors; Transforming Growth Factor beta

Restenosis following angioplasty involves processes that may be influenced by local production of cytokines. We investigated the expression of active and total transforming growth factor beta (TGFbeta) following porcine coronary angioplasty (PTCA), and have correlated this with the expression of potential in vivo activators of TGFbeta: mannose-6-phosphate/insulin-like growth factor-II (M6P/IGF-II) receptor and thrombospondin-1.. Oversized porcine PTCA was performed and the arteries excised after selected intervals. Levels of in situ active and total (active plus latent) TGFbeta were determined using a modified plasminogen activator-inhibitor/luciferase bioassay.. Levels of active TGFbeta significantly increased 2 h to 7 days after angioplasty, compared to non-injured controls. Levels returned to baseline by 28 days. Active TGFbeta in tissues adjacent to the injured artery did not change. Total TGFbeta was significantly higher than controls 2-6 h after injury. M6P/IGF-II receptor mRNA was upregulated between 6 h and 3 days after injury, with protein detectable at 3-28 days. Thrombospondin-1 was detected between 1 h and 14 days.. We conclude that balloon injury causes an early rapid increase in levels of active TGFbeta, that correlates with the expression of TGFbeta activators. Thus, TGFbeta is a good potential target for anti-restenotic therapies.

Topics: Angioplasty, Balloon, Coronary; Animals; Blotting, Western; Coronary Disease; Coronary Vessels; Immunoenzyme Techniques; Receptor, IGF Type 2; Recurrence; Swine; Thrombospondin 1; Time Factors; Transforming Growth Factor beta

Topics: Arteriosclerosis; Coronary Disease; Echocardiography; Female; Follow-Up Studies; Genotype; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Time Factors; Transforming Growth Factor beta; Ventricular Dysfunction, Left

The multifunctional cytokine transforming growth factor- (TGF) beta1 is thought to play a role in the pathogenesis of graft vascular disease (GVD). Polymorphisms at codon 10, (Leu10-->Pro) and codon 25 (Arg25-->Pro) in the signal sequence of the TGF-beta1 gene regulate the production and secretion of the protein. We investigated whether these polymorphisms are risk factors for the development of GVD after clinical heart transplantation.. TGF-beta1 polymorphisms, Leu10-->Pro and Arg25-->Pro, were determined in DNA from heart transplant recipients (n=252) and their donors (n=213), using sequence-specific oligonucleotide probing. GVD was angiographically diagnosed 1 year after transplantation. In addition other potential risk factors including underlying disease, recipient and donor age, recipient and donor gender, number of acute rejections in the first year, cold ischemia time, and HLA mismatches were analyzed by univariate and multivariate logistic regression analysis.. Univariate analysis showed that the recipient TGF-beta1 polymorphism Leu10-->Pro, (P=0.056, chi2 test), underlying disease (P=0.01, chi2 test), number of acute rejections in the first-year (P=0.03, analysis of variance), and donor age (P<0.001, analysis of variance) were risk factors for the development of GVD. The TGF-beta1 Arg25-->Pro polymorphism was not a risk factor. Also in the multivariate analysis, the recipient TGF-beta1 codon 10 polymorphism was associated with GVD, with patients homozygous for Pro at greatest risk (odds ratio 7.7, P=0.03). Apart for the recipient TGF-beta1 Leu10-->Pro polymorphism, donor age appeared to be an independent risk factor for the development of GVD at 1 year. Patients with older donor hearts were at greater risk than patients receiving grafts from younger donors (odds ratio 1.1/year, P<0.001).. Recipient TGF-beta1 Leu10-->Pro polymorphism and higher donor age are independent risk factors for the development of GVD after clinical heart transplantation.

Topics: Adult; Aged; Aging; Codon; Coronary Disease; Genetic Predisposition to Disease; Graft vs Host Disease; Heart Transplantation; Humans; Middle Aged; Polymorphism, Genetic; Time Factors; Tissue Donors; Transforming Growth Factor beta; Transforming Growth Factor beta1

Cardiac allograft vasculopathy is a frequent sequel to cardiac transplantation, but the role of cytokines on the subsequent development of vasculopathy is still largely unknown.. We retrospectively studied 172 heart transplant recipients to investigate the relationship between the development of vasculopathy and various factors including the presence of transforming growth factor (TGF-beta) in the graft. Endomyocardial biopsy specimens were stained with antibodies for TGF-beta and CD+68, and a TGF-beta staining score was derived. Vasculopathy was diagnosed by angiography and rejection was graded according to the International Society of Heart and Lung Transplantation classification. TGF-beta(1) genotype was determined by polymerase chain reaction analysis of DNA.. After a mean follow-up period of 68 +/- 32 months, the prevalence of significant vasculopathy was 52%. The TGF-beta staining score was higher in patients with more severe vasculopathy (95% confidence interval = 8.9-12.1) than in those who showed minimal or mild vasculopathy score changes of more than 7 (95% confidence interval = 3.4-5.1), P =.0001. TGF-beta expression correlated with the degree of vasculopathy (r = 0.73, P <.0007) during the study period. Risks for vasculopathy were recipient homozygous TGF-beta genotype, recurrent rejection, recipient history of ischemic heart disease, donor male sex, old donor age (years), and donor history of subarachnoid hemorrhage.. A strong association exists between the expression of TGF-beta in cardiac biopsy specimens and the development of vasculopathy. TGF-beta in the cardiac allograft is related to its genotype and to the number of rejection episodes. Strategies to down-regulate TGF-beta production might improve the outcome of cardiac allografts.

Topics: Adult; Biopsy, Needle; Coronary Angiography; Coronary Disease; Endocardium; Female; Genotype; Heart Transplantation; Humans; Immunohistochemistry; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Retrospective Studies; Risk Factors; Transforming Growth Factor beta

Expression of transforming growth factor-beta1 (TGF-beta1) is central to vascular repair due to its effects on smooth muscle cell, monocyte/macrophage, leucocyte, and extracellular matrix accumulation and proliferation. Genetic polymorphism at position +915 of the TGF-beta1 gene determines the degree of cytokine production in response to injury. We investigated this allelic variation on the development of cardiac transplant-related coronary vasculopathy (CV).. Using sequence-specific primers to the TGF-beta1 gene region of interest, a polymerase chain reaction (PCR) and gel electrophoresis identified the genotype in 129 cardiac transplant recipients. An association was sought between the presence of a high- (GG) or low/intermediate-producing (CC/GC) genotype and the development of coronary vasculopathy diagnosed by coronary angiography.. C allele carriers made up 10.9% of the recipient population but were significantly less likely to develop coronary vasculopathy (p = 0. 0361). Mean time to diagnosis was 1240.5 days in G homozygotes relative to 2266.5 days in C allele carriers (p = 0.002). Pre- and 1-year posttransplant clinical variables were equivalent between the 2 groups. Multivariate analysis identified the GG genotype (p = 0. 042, hazard ratio 3.01, [95% CI, 1.056-10.99]), donor age (p = 0.002, hazard ratio 1.063, [95% CI, 1.029-1.097]), and number of acute-rejection episodes of grade 3 or greater in the first year (p = 0.029, hazard ratio 1.11, [95% CI, 1.05-1.26]) as significant predictors of vasculopathy.. This study demonstrates a correlation between a high-producing TGF-beta1 genotype and an earlier onset of cardiac-transplant coronary vasculopathy. This gives an important insight into the pathophysiology of cardiac transplant vasculopathy and suggests new treatment options.

Topics: Adult; Alleles; Coronary Angiography; Coronary Disease; DNA; DNA Primers; Genetic Markers; Genotype; Heart Transplantation; Humans; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Prognosis; Retrospective Studies; Transforming Growth Factor beta

Topics: Coronary Disease; Female; Humans; Male; Transforming Growth Factor beta

Topics: Aged; Angioplasty, Balloon; Coronary Disease; Graft Occlusion, Vascular; Humans; Middle Aged; Plasminogen Activator Inhibitor 1; Transforming Growth Factor beta; Transforming Growth Factor beta1

The long-term success of cardiac transplantation is limited by graft coronary artery disease (GCAD). Antisense oligonucleotides (ASs) to proliferating cell nuclear antigen (PCNA) and Cdc2 kinase (Cdc2 k) can arrest cell cycle progression and inhibit neointimal hyperplasia. Transforming growth factor-ss(1) (TGF-ss(1)) has been implicated in vascular smooth muscle cell (VSMC) activation. The role of TGF-ss(1) in GCAD remains unclear. We hypothesized that ASs to PCNA and Cdc2 k would inhibit VSMC proliferation and GCAD.. In vitro VSMC proliferation was determined after pretreatment with AS solution or medium alone followed by angiotensin II stimulation. PVG-to-ACI rat heterotopic cardiac transplantation procedures were performed after ex vivo pressure-mediated transfection of ASs to PCNA and Cdc2k or saline alone. At postoperative days 30, 60, and 90, allografts were assessed for GCAD, percent neointimal macrophages and VSMCs, and TGF-ss(1) activity. AS pretreatment significantly attenuated VSMC proliferation. At postoperative day 90, percent affected arteries, percent occlusion, and intima-media ratio demonstrated severe GCAD in saline-treated allografts, whereas these parameters were significantly lower in AS-treated allografts. Percent neointimal macrophages and VSMCs was reduced in AS-treated allografts. TGF-ss(1) activity was increased in saline compared with AS-treated allografts and nontransplanted heart controls.. ASs to PCNA and Cdc2 k inhibit VSMC proliferation in vitro and reduce GCAD, percent neointimal VSMCs and macrophages, and TGF-ss(1) activity in vivo. TGF-ss(1) may play a "response to injury" role in the development of GCAD. The prevention of GCAD via AS inhibition of cell cycle regulatory genes before reperfusion may offer a useful clinical alternative to current therapeutic strategies.

Topics: Actins; Animals; CDC2 Protein Kinase; Cell Division; Cells, Cultured; Coronary Disease; Disease Models, Animal; Heart Transplantation; Humans; Immunohistochemistry; Macrophages; Male; Muscle, Smooth, Vascular; Oligonucleotides, Antisense; Polymerase Chain Reaction; Proliferating Cell Nuclear Antigen; Rats; Rats, Inbred ACI; Rats, Sprague-Dawley; Tetrazolium Salts; Thiazoles; Transcription, Genetic; Transforming Growth Factor beta; Transforming Growth Factor beta1

The purpose of this study was to determine the efficacy and the possible mechanism of action of a recently synthesized drug, TAS-301 [3-bis(4-methoxyphenyl)methylene-2-indolinone], on stenosis after balloon overstretch injury of porcine arteries. We measured the diameter of vessels by angiography and conducted histological analysis. The oral administration of TAS-301 kept dilated the angiographic luminal diameter of injured segment 4 weeks after overstretch injury and reduced calculated stenosis ratio in a dose-dependent manner, significantly reducing it at doses of 30 and 100 mg/kg. Histopathological analysis showed that TAS-301 significantly reduced the adventitial area at doses of 30 and 100 mg/kg with moderate reduction of the neointimal area, resulting in the larger residual lumen. In an in vitro assay, TAS-301 dose dependently inhibited the proliferation of adventitial fibroblasts stimulated by basic fibroblast growth factor or transforming growth factor-beta(1). In addition, the drug reduced adventitial fibroblast-mediated three-dimensional collagen gel contraction. These findings indicate that TAS-301, the first compound developed for targeting the constrictive remodeling, showed a high inhibitory potency on coronary artery stenosis of micropigs after injury, mainly due to inhibition of adventitial fibroblast proliferation and of the contractile ability of myofibroblasts. Our results suggest the strong possibility that TAS-301 may be efficacious for prevention of restenosis after angioplasty and the need to examine the therapeutic usefulness of this drug in clinical trials.

Topics: Angioplasty, Balloon, Coronary; Animals; Cell Division; Coronary Angiography; Coronary Disease; Dose-Response Relationship, Drug; Fibroblast Growth Factor 2; Fibroblasts; Indoles; Male; Recurrence; Swine; Transforming Growth Factor beta

Tranilast (SB 252218) is a compound initially identified as an anti-atopic agent. Recently the compound has demonstrated clear beneficial effects in animal models of restenosis. Here we confirm tranilast has broad and profound effects on human monocytes, which could contribute to the vascular antifibrotic activity. Tranilast exhibited significant immunomodulatory activity inhibiting endotoxin-induced prostaglandin E(2) (PGE(2); IC(50) = approximately 1-20 microM), thromboxane B(2) (IC(50) = approximately 10-50 microM), transforming growth factor-beta1 (TGF-beta1; IC(50) = approximately 100-200 microM), and interleukin-8 (IC(50) = approximately 100 microM) formation, but had no effect on tumor necrosis factor-alpha. Interleukin-12 and -18-induced interferon-gamma formation by monocytes was also attenuated by tranilast. A23187-induced monocyte leukotriene C(4) or PGE(2) formation was inhibited by tranilast at IC(50) values of 10-40 microM and 2-20 microM, respectively, incubated with or without exogenous arachidonic acid. Interestingly, tranilast (up to 1000 microM) had no direct effects on cyclooxygenase I or II activity, nor did it have significant effects on human type IIA 14 kDa or type IV 85 kDa phospholipase A(2) activity. Furthermore, tranilast had no effect on endotoxin-induced cyclooxygenase II protein expression, suggesting tranilast modulates eicosanoid production and release by an as yet unidentified mechanism. Alternatively, the expression of TGF-beta1 was inhibited by tranilast but found to be due in part to inhibition of PGE(2) because exogenous PGE(2) could abrogate tranilast-mediated inhibition of TGF-beta1. Taken together, although a reported direct inhibitor of fibroblast proliferation, we show tranilast also attenuates the proinflammatory activity of human monocytes, adding to its potential efficacy as a therapeutic agent in restenosis.

Topics: Arachidonic Acid; Calcium; Coronary Disease; Cyclooxygenase 2; Dinoprostone; Humans; Isoenzymes; Leukotriene C4; Membrane Proteins; Monocytes; ortho-Aminobenzoates; Phospholipases A; Prostaglandin-Endoperoxide Synthases; Transforming Growth Factor beta

to compare patients with abdominal aortic aneurysm (AAA) and aortic occlusive disease (AOD) with regard to risk factors for atherosclerosis, co-morbid conditions and inflammatory activity.. a total of 155 patients undergoing abdominal aortic surgery between January 1993 and October 1997: 82 (53%) had aneurysmal disease and 73 (47%) had occlusive disease. Principal risk factors were compared: age; gender; smoking; hypertension; hyperlipidaemia; diabetes mellitus; severe peripheral vascular disease (PVD) and ischaemic heart disease. Aortic wall tissue samples were obtained during surgery. A prospective blind analysis was performed for the presence of inflammatory cytokines TNF-alpha, IL-1 beta, IL-6 and TGF-beta.. the average age of AAA patients was 74 years (50-88), while that of AOD patients was 61 years (43-82) (p<0.0001). Diabetes mellitus was found to be much more prevalent in the AOD group (p<0.001), while hypertension and severe PVD were more prevalent in the AAA group (p<0.001). No differences were found concerning any of the risk factors. Inflammatory cytokine activity: AAA tissue samples contained significantly higher mean TNF-alpha and IL-6 levels compared to the AOD samples (5.6+/-2.7 x 10 E-4 vs. 4.4+/-2.7 x 10 E-5 atmoles/microl (p=0. 01), and 0.6+/-0.4 vs. 0.01+/-0.006 atmoles/microl (p=0.02) respectively). No differences were found related to IL-1 beta and TGF-beta.. (1) Patients with AAA have fewer atherosclerotic risk factors than do patients with AOD. (2) Patients with AAA and AOD have significantly different inflammatory activity. (3) The data supports the hypothesis that AAA and AOD are probably two different pathological entities.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal; Aortic Diseases; Coronary Disease; Diabetes Complications; Female; Humans; Hyperlipidemias; Hypertension; Interleukin-1; Interleukin-6; Male; Middle Aged; Polymerase Chain Reaction; Prospective Studies; Risk Factors; Sex Factors; Smoking; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Diseases

The degree of cellularity in vascular lesions is determined by the balance between the migration and proliferation of cells relative to their rate of egress and apoptosis. Transforming growth factor-beta(1) can act as a potent antiproliferative and apoptotic factor for proliferating vascular cells. Our laboratory has previously identified cells cultured from human vascular lesions that are resistant to the antiproliferative effect of TGF-beta(1) due to an acquired mutation in the Type II receptor for TGF-beta(1). In the present studies, the expression of the Type I and II receptors in coronary and carotid atherosclerotic lesions was analysed by immunostaining, RT-PCR, and in situ RT-PCR. Levels of the Type I and Type II receptors varied widely within lesions, with the highest levels in the fibrous cap and at discrete foci within the lesion. Regions of smooth muscle-like cells (SMC) were commonly found that were Type I positive but Type II receptor negative. In 43 cell lines cultured from 126 human lesions, 84% of the lesion-derived cell (LDC) cultures exhibited functional resistance to the antiproliferative effect of TGF-beta(1). This resistance was conferred against TGF-beta(1), TGF-beta(2), and TGF- beta(3), but not interferon-gamma or mimosine. While normal SMC exhibited a four-fold increase in the rate of apoptosis after TGF- beta(1) treatment, most LDC were resistant to apoptosis in response to TGF-beta(1). Resistant cells exhibited selective loss of Type II receptor expression, and retroviral transfection of Type II receptor cDNA partially corrected the functional deficit. Thus, resistance to apoptosis may lead to the slow proliferation of resistant cell subsets, thereby contributing to the progression of atherosclerotic and restenotic lesions.

Topics: Activin Receptors, Type I; Apoptosis; Arteriosclerosis; Atherectomy; Carotid Stenosis; Cell Division; Cloning, Molecular; Coronary Disease; Endarterectomy, Carotid; Humans; Immunohistochemistry; Models, Cardiovascular; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Recombinant Proteins; Recurrence; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcription, Genetic; Transfection; Transforming Growth Factor beta

Topics: Angioplasty, Balloon, Coronary; Case-Control Studies; Coronary Disease; Humans; Plasminogen Activator Inhibitor 1; Recurrence; Transforming Growth Factor beta

Topics: Coronary Disease; Gene Expression Regulation; Graft vs Host Disease; Heart Transplantation; Humans; Myocardium; Platelet-Derived Growth Factor; Postoperative Complications; RNA, Messenger; Time Factors; Transcription, Genetic; Transforming Growth Factor beta

This study was to determine whether the growth factors platelet-derived growth factor-alpha (PDGF-alpha) and transforming growth factor-beta1 (TGF-beta1) contribute to the development of graft vascular disease (GVD) after clinical heart transplantation. We analysed intragraft PDGF-alpha and TGF-beta1 messenger RNA (mRNA) expression levels by competitive template reverse transcriptase polymerase chain reaction (RT-PCR). Endomyocardial biopsies (EMB) were obtained at 1 and 9 months post-transplant from cardiac allograft recipients with (n = 11) and without (n = 11) angiographic evidence of GVD at 1 year. In 1-month EMB, comparable TGF-beta1 mRNA levels were found in patients with and without GVD at 1 year (p = 0.84, Mann-Whitney U-test). In contrast, in 9-month EMB during the development of GVD, intragraft mRNA levels of both PDGF-alpha (p = 0.08) and TGF-beta1 (p = 0.03) were higher in patients with GVD after the first year compared to patients without GVD. These results suggest that intragraft PDGF-alpha and TGF-beta1 play a role in the pathogenesis of accelerated GVD after clinical heart transplantation.

Topics: Adult; Coronary Disease; Female; Graft vs Host Disease; Heart Transplantation; Humans; Male; Middle Aged; Receptor, Platelet-Derived Growth Factor alpha; Transforming Growth Factor beta

We examined the relative contributions of foreign body granulation and de novo lesions to neointimal hyperplasia in atherectomized specimens of restenosis after coronary stenting.. Clinicopathological studies have suggested that smooth muscle cell (SMC) hyperplasia is the most likely cause of restenosis after coronary stenting. It is not yet fully understood how SMC hyperplasia occurs or how SMCs stimulation can lead to intimal hyperplasia. Although inflammation has been postulated to be a major contributor to restenosis after coronary stenting, there is a paucity of data on the relationsip between inflammation and subsequent neointimal formation in humans. Only in a porcine experimental model of stent restenosis, foreign body granulation tissue as a cause of inflammation in stent restenosis was reported.. Tissue specimens were retrieved by directional atherectomy from 11 patients in whom stent restenosis developed after percutaneous revascularization of coronary artery disease. For specimens preserved in 10% buffered formalin, analysis of cellular composition was performed quantitatively after cell-specific immunostaining, i.e. CD68, UCHL-1, HLA-DR, smooth muscle actin, vimentin, desmin, PCNA and TGF-beta.. Five of the 11 patients showed granulation tissues 3-6 months after stent implantation, of whom 3 patients revealed foreign body multinucleated giant cells around the stent struts where PCNA- and vimentin-positive SMCs were demonstrated. Calcification and de novo lesions in medial and adventitial tissues were observed in 3 other patients, and fresh and/or organized thrombi were documented in 3 of the 11 patients.. These findings support the notion that stent restenosis results from SMC hyperplasia and suggest that the foreign body granulation tissue against metals of the stents and de novo lesions could play an important role in chronic inflammation leading to intimal hyperplasia and subsequently to stent restenosis in some patients. Clinicians should thus consider whether a patient may be allergic to stent components with unknown reaction, e.g. haptens.

Topics: Aged; Atherectomy, Coronary; B-Lymphocytes; Calcinosis; Coronary Angiography; Coronary Disease; Female; Giant Cells, Foreign-Body; Graft Occlusion, Vascular; Granuloma, Foreign-Body; HLA-DR Antigens; Humans; Hyperplasia; Immunoenzyme Techniques; Male; Microfilament Proteins; Middle Aged; Muscle, Smooth, Vascular; Proliferating Cell Nuclear Antigen; Recurrence; Reoperation; Stents; T-Lymphocytes; Transforming Growth Factor beta; Tunica Intima

To determine mechanisms that trigger graft vascular disease (GVD) after heart transplantation, we studied parameters that reflect both early and late intragraft allogeneic reactions.. With reverse transcriptase-polymerase chain reaction analysis, mRNA expression of interleukin-2 (IL-2), interleukin-4, interleukin-6, interleukin-10, interferon-gamma, platelet-derived growth factor-alpha, and transforming growth factor-beta was measured in endomyocardial biopsy (EMB) specimens obtained from 34 recipients during the first acute rejection episode (n = 29) or at a comparable time after transplantation for patients without rejection (n = 5) and at time of assessment of GVD by coronary angiography at 1 year (n = 34).. At the time of assessment of GVD, mRNA expression of IL-2, interleukin-4, and interleukin-6 were barely detectable, whereas messenger coding for interferon-gamma, interleukin-10, transforming growth factor-beta, and platelet-derived growth factor-alpha genes were constitutively expressed. Moreover, intragraft mRNA patterns of cytokines and growth factors between patients with GVD (n = 17) or without GVD (n = 17) were comparable. In contrast, during the first acute rejection episode a completely different pattern was found. Development of GVD was associated with IL-2 mRNA expression and not with the other cytokines analyzed. IL-2 mRNA was present in 77% of rejection EMB specimens obtained from patients with GVD versus 33% of the EMB specimens obtained from patients without GVD (p = 0.03) and not detectable in EMB specimens obtained from patients with no rejection. Also nonimmunologic risk factors such as longer ischemia time (median 193 vs 141 minutes; p = 0.002) and higher donor age (median 32 vs 23 years; p = 0.02) were associated with GVD. But no relation was found between these nonimmunologic risk factors and IL-2-positive acute rejections.. Nonspecific risk factors and IL-2-positive rejections may independently trigger GVD after clinical heart transplantation.

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Biopsy; Case-Control Studies; Coronary Angiography; Coronary Disease; Female; Graft Rejection; Heart Transplantation; Humans; Interferon-gamma; Interleukin-10; Interleukin-2; Interleukin-4; Interleukin-6; Ischemia; Male; Middle Aged; Platelet-Derived Growth Factor; Polymerase Chain Reaction; Risk Factors; RNA, Messenger; Transforming Growth Factor beta; Transplantation, Homologous

Topics: Coronary Disease; Enzyme-Linked Immunosorbent Assay; Humans; Sensitivity and Specificity; Transforming Growth Factor beta

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

1. Transforming growth factor-beta1 is a cytokine with a very wide spectrum of biological activities. Previous studies have shown that it is involved in a number of physiological and pathological processes including heart disease. In our study we aimed to scan the transforming growth factor-beta1 locus for polymorphisms and to identify haplotypes significantly associated with a predisposition to coronary atherosclerosis.2. Two patient groups comprising 244 angiographically normal individuals and 655 patients with coronary artery disease were recruited from London and Sheffield. DNA samples from these subjects were screened for mutations in the transforming growth factor-beta1 locus and all subjects were genotyped by a coupled polymerase chain reaction-restriction enzyme digestion method.3. Five polymorphisms have been identified in the transforming growth factor-beta1 gene at positions G-800A, C-509T in the promoter region, Leu10-->Pro, Arg25-->Pro in exon 1 and Thr263-->Ile in exon 5. No significant difference in frequencies for any of the five polymorphisms was found between controls and patients with coronary artery disease. Similarly, there was no correlation between these polymorphisms and hypertension.4. The genotypes of all the individuals participating in the study were assigned to seven main haplotypes of the transforming growth factor-beta1 locus. Based on species comparison data we propose that GCCGC is the ancestral haplotype in humans.5. Our data suggest that these transforming growth factor-beta1 polymorphisms are not associated with coronary artery disease and therefore their presence alone would not be a genetic risk factor for predisposition to coronary artery disease.

Topics: Case-Control Studies; Chi-Square Distribution; Coronary Disease; Female; Genetic Markers; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Linkage Disequilibrium; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Risk Factors; Transforming Growth Factor beta

Topics: Coronary Disease; Genetic Predisposition to Disease; Humans; Hypertension; Myocardial Infarction; Polymorphism, Genetic; Transforming Growth Factor beta

Cardiovascular surgery with extracorporeal circulation causes a systemic inflammatory response, which can lead to organ failure and increased postoperative morbidity. Advances in knowledge about the interactions between markers of cellular and humoral immunity involved in the inflammatory response to cardiopulmonary bypass (CPB) may reduce the deleterious effects and improve the outcome for patients undergoing cardiac surgery.. To determine the release of immunoinhibiting cytokines during CPB, we measured plasma levels of interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) in 30 patients undergoing elective coronary artery bypass grafting. Arterial blood samples were collected at eight time points before, during and after CPB, using a standardized ELISA-technique.. Plasma IL-10 and TGF-beta increased significantly after weaning off CPB (P < 0.05) and peaked respectively at time of skin closure (IL-10, 308 +/- 180 pg/ml; TGF-beta, 1860 +/- 906 pg/ml; mean peak +/-S.D.). Postoperatively, 6 h, IL-10 decreased to 19.8 +/- 9.8 pg/ml (P < 0.05) and TGF-beta decreased to 1133 +/- 547 pg/ml (P < 0.05).. Both cytokines are major immunoregulatory factors with negative influence on T cell-mediated immunologic response. The significantly elevated levels at the end of CPB indicate that IL-10 and TGF-beta may be important factors of immunologic dysregulation following CPB.

Topics: Adult; Aged; Cardiopulmonary Bypass; Coronary Artery Bypass; Coronary Disease; Humans; Interleukin-10; Male; Middle Aged; Postoperative Complications; Risk Factors; Systemic Inflammatory Response Syndrome; Transforming Growth Factor beta

Transforming growth factor beta 1 (TGF-beta 1), a multifunctional cytokine, is involved in many physiological and pathological processes and possibly in atherogenesis.. We explored the association between circulating plasma TGF-beta 1 measured by ELISA and coronary artery disease (CAD) assessed angiographically in 371 Caucasian patients (269 men and 102 women) aged < or = 65 years.. While mean +/- s.e.m total TGF-beta 1 was not different among patients with (56.9 +/- 1.5 ng/ml) or without (54.6 +/- 2.8 ng/ml) angiographically demonstrable CAD, naturally active TGF-beta 1 was significantly higher in CAD patients (1.74 +/- 0.18 vs 0.96 +/- 0.17 ng/ml, P < 0.01). Active TGF-beta 1 increased with the number of major coronary arteries with more than 50% luminal obstruction (P < 0.01) and patients with triple vessel disease had twice the level of those with no or mild vessel disease (2.15 +/- 0.46 vs 1.12 +/- 0.14 ng/ml, P < 0.001). We found no relationship between TGF-beta 1 and Lp(a), but TGF-beta 1 was significantly correlated with circulating fibrinogen (r = 0.178, P = 0.005) and fasting glucose (r = 0.177, P = 0.007) levels.. Our study identifies an increase in active TGF-beta 1 levels with both the occurrence and severity of CAD which is independent of standard CAD risk factors. This may reflect a 'double-edged sword' effect of TGF-beta 1 in that it may reduce atherogenesis by inhibiting smooth muscle cell proliferation but, when there is ongoing vessel wall injury, enhance it by promoting excessive extracellular matrix accumulation. The outcome could represent a complex balance between these two competing influences.

Topics: Aged; Biomarkers; Blood Glucose; Coronary Angiography; Coronary Disease; Enzyme-Linked Immunosorbent Assay; Female; Fibrinogen; Humans; Male; Middle Aged; Smoking; Transforming Growth Factor beta

Endothelial injury, manifest by increased protein leak and decreased endothelium-dependent relaxation, occurs during reperfusion after ischemia. Transforming growth factor-beta (TGF-beta) has been shown to improve endothelium-dependent relaxation and reduce infarct size after short periods (from 20 min to 4.5 h) of reperfusion even when administered 24 h before the ischemic period. However, whether this represents a transient delay in the process leading to endothelial injury or prevention of injury has not been clear. To examine this issue, we measured protein leak, an index of coronary microvascular permeability, and endothelium-dependent relaxation, a measure of coronary endothelial function, after brief (1-h) and lengthy (48-h) reperfusion periods in dogs treated 30 min before ischemia with TGF-beta (30 microg/kg, i.v.) and control dogs. The left anterior descending coronary artery (LAD) was ligated for 1 h followed by 1 h of reperfusion (n = 10) or 48 h of reperfusion (n = 12). Protein leak was assessed by a dual-isotope technique by using radiolabeled transferrin and erythrocytes, and endothelium-dependent relaxation was assessed in epicardial coronary rings by using adenosine diphosphate (ADP), an endothelium-dependent vasodilator, and sodium nitroprusside (SNP), an endothelium-independent dilator. In control animals, there was a marked increase in the protein leak index (PLI) in the infarct zone (8.3 +/- 1.4 in 1-h dogs, and 8.7 +/- 0.9 in 48-h dogs) compared with the nonischemic myocardium (3.1 +/- 0.8 at 1 h, and 3.8 +/- 0.9 at 48 h). In TGF-beta treated dogs, there was a marked improvement in PLI in the infarct zone in 1-h dogs (PLI, 4.1 +/- 1.1; p < 0.05; or a 50% reduction compared with untreated dogs). However, the 48-h dogs treated with TGF-beta failed to demonstrate an improvement in PLI (PLI, 8.5 +/- 0.9; p = NS). Endothelium-dependent relaxation was impaired in the LAD in control dogs, and treatment with TGF-beta failed to improve relaxation after 1 or 48 h of reperfusion. Microvascular permeability was increased and endothelium-dependent relaxation was decreased after ischemia at both 1 and 48 h of reperfusion. Pretreatment with TGF-beta reduced the increase in permeability at 1 h of reperfusion but not at 48 h.

Topics: Animals; Capillary Permeability; Coronary Circulation; Coronary Disease; Coronary Vessels; Dogs; Electrocardiography; Endothelium, Vascular; Male; Muscle Proteins; Myocardial Reperfusion Injury; Myocardium; Peroxidase; Transforming Growth Factor beta; Vasodilation; Vasodilator Agents

Cytomegalovirus has been implicated in the development of allograft vasculopathy in heart transplant recipients. Given that allograft vasculopathy is a form of chronic rejection, it is conceivable that cytomegalovirus somehow alters the allogeneic response to the vasculature. Prior work has demonstrated that smooth muscle cells (SMCs) are highly permissive for cytomegalovirus and exhibit cytopathologic characteristics and alterations in MHC class I antigens in response to cytomegalovirus at a high multiplicity of infection (MOI).. To determine whether cytomegalovirus at low, more clinically relevant MOI, can alter SMCs phenotypically, human aortic SMCs were infected with approximately 1 plaque forming units/3000 cells of cytomegalovirus strain AD169.. One week after infection, human aortic SMCs (compared with human foreskin fibroblasts) demonstrated no cytopathologic characteristics (n = 6), released reduced amounts of intact virion into the culture media (assessed by exposing naive monolayers of human foreskin fibroblasts to media and staining for cytomegalovirus immediate-early antigen, n = 3), yet had at least, if not greater detectable total cytomegalovirus vital DNA levels. Infected HASMCs uniformly increased their expression of MHC class I antigen by 55% +/- 21% above constitutive levels (assessed by flow cytometry (n = 5, p < 0.0001). Cytomegalovirus infection resulted in an increase in interleukin-6 mRNA expression compared to control (297 +/- 63 vs 188 +/- 50, respectively; p = 0.02, n = 6) and reduced the expression of transforming growth factor-beta mRNA (802 +/- 152 vs 1201 +/- 236, respectively; p = 0.05).. These data suggest that low MOI of cytomegalovirus can infect SMCs without producing cell cytolysis and, in spite of this lack of overt infection, modulate cell surface antigens and cytokine mRNA levels that can influence allogeneic responses.

Topics: Antigens, Viral; Aortic Diseases; Cells, Cultured; Chronic Disease; Coloring Agents; Coronary Disease; Culture Media; Cytokines; Cytomegalovirus; Cytomegalovirus Infections; Cytopathogenic Effect, Viral; DNA, Viral; Fibroblasts; Gene Expression Regulation, Viral; Graft Rejection; Heart Transplantation; Histocompatibility Antigens Class I; Humans; Immediate-Early Proteins; Interleukin-6; Muscle, Smooth, Vascular; Phenotype; RNA, Messenger; Transforming Growth Factor beta; Transplantation, Homologous; Virion; Virus Replication

Transforming growth factor-beta (TGF-beta) plays an important role in vascular lesion formation and possibly the renarrowing process ("restenosis") that occurs after balloon angioplasty. Secreted in a latent form by most cells, TFG-beta requires enzymatic conversion before it is biologically active. TGF-beta-inducible gene h3 (beta ig-h3) is a novel molecule that is induced when cells are treated with TGF-beta1. This study examined the expression of beta ig-h3 in normal and diseased human vascular tissue. To determine the expression pattern of beta ig-h3 in human arteries, immunocytochemistry was performed on tissue sections from (1) normal internal mammary arteries, (2) the proximal left anterior descending coronary artery (with minimal intimal thickening) of 15 patients aged 18 to 40 years, (3) primary and restenotic coronary lesions from 7 patients, and (4) fresh directional atherectomy tissue from 11 patients. A polyclonal antibody consistently immunodetected beta ig-h3 protein in endothelial cells of all vascular tissue. In normal coronary arteries of young individuals, beta ig-h3 protein was absent from the intima and media but was found in the subendothelial smooth muscle cells of some arteries with modest intimal thickening. In diseased arteries beta ig-h3 protein was more abundant in the intima than the media. Restenotic coronary lesions tended to show higher levels of immunodetectable beta ig-h3 protein, especially in areas of dense fibrous connective tissue. Beta ig-h3 protein was immunodetected in the cytoplasm of plaque macrophages as well as smooth muscle and endothelial cells. By using in situ hybridization on fresh directional atherectomy specimens, we found beta ig-h3 mRNA to be overexpressed by plaque macrophages and smooth muscle cells. Nondiseased human internal mammary arteries also expressed beta ig-h3 mRNA in endothelial cells but not in the smooth muscle cells of the normal intima and media. These results document the expression of beta ig-h3 in diseased human arterial tissue and support the hypothesis that active TGF-beta plays a role in atherogenesis and restenosis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; CHO Cells; Coronary Disease; Coronary Vessels; Cricetinae; Female; Gene Expression Regulation; Humans; Macrophages; Male; Mammary Arteries; Muscle, Smooth, Vascular; Recurrence; RNA, Messenger; Transforming Growth Factor beta

Transforming growth factor-beta (TGF-beta) is a potent inducer of extracellular matrix production and of fibrogenesis and has been associated with the occurrence of diabetic micro- and macrovascular complications. Our aim was to determine whether circulating levels of TGF-beta 1 are altered in NIDDM and, if so, whether they are correlated with blood glucose and show an association with diabetic complications.. Plasma levels of TGF-beta 1 were determined by enzyme-linked immunosorbent assay in 44 NIDDM patients and 28 control subjects of comparable age and weight and were correlated with parameters of metabolic control and the occurrence of micro- and macrovascular complications.. TGF-beta 1 was significantly elevated in NIDDM (7.9 +/- 1.0 ng/ml), as compared with control subjects (3.1 +/- 0.4 ng/ml, P < 0.001) and correlated with glycosylated hemoglobin (r2 = 0.42; P < 0.001). Thrombocyte levels of TGF-beta 1 were similar in control subjects (54 +/- 7 pg/ml, n = 16) and diabetic patients (61.6 +/- 18 pg/ml, n = 13; P = 0.357). Elevated TGF-beta 1 levels were associated with retinopathy and neuropathy.. We conclude that plasma levels of TGF-beta 1 are elevated in NIDDM patients and may be related to average blood glucose. Preliminary data suggest that they may contribute to the occurrence of diabetic complications.

Topics: Aged; Biomarkers; Blood Glucose; Coronary Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Hypertension; Male; Middle Aged; Reference Values; Regression Analysis; Statistics, Nonparametric; Transforming Growth Factor beta

To examine localisation of tumour necrosis factor (TNF alpha) and transforming growth factor beta (TGF beta) mRNA synthesis in human coronary artery atheromatous plaques, to explore how synthesis of these cytokines relates to distribution of macrophages and smooth muscle cells, and to correlate this with plaque micro-environments.. In situ hybridisation with digoxigenin-labelled sense and anti-sense riboprobes was used, combined with immunohistochemistry to detect TNF alpha protein, macrophage, lymphocyte and smooth muscle cell markers.. In the intimal plaque TNF alpha mRNA is synthesised by monocytes/macrophages as well as by smooth muscle cells. Both TNF alpha and TGF beta mRNAs were present at the margins of the lesions and in reactive areas, where there was little lipid and fibrosis. Focal aggregates of macrophages in the adventitia expressed both TNF alpha mRNA and protein and TGF beta mRNA.. Synthesis of these two cytokines by macrophages as well as smooth muscle cells contributes to the pathobiology of the plaque and that this is part of the 'reaction to injury', rather than a feature of a specific cell, or a specific layer, within the vessel wall.

Topics: Coronary Disease; Cytokines; Humans; Immunohistochemistry; In Situ Hybridization; Macrophages; Muscle, Smooth, Vascular; RNA, Messenger; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Atherosclerosis and postangioplasty restenosis may result from abnormal wound healing. The present studies report that normal human smooth muscle cells are growth inhibited by TGF-beta1, a potent wound healing agent, and show little induction of collagen synthesis to TGF-beta1, yet cells grown from human vascular lesions are growth stimulated by TGF-beta1 and markedly increase collagen synthesis. Both cell types increase plasminogen activator inhibitor-1 production, switch actin phenotypes in response to TGF-beta1, and produce similar levels of TGF-beta activity. Membrane cross-linking of 125I-TGF-beta1 indicates that normal human smooth muscle cells express type I, II, and III receptors. The type II receptor is strikingly decreased in lesion cells, with little change in the type I or III receptors. RT-PCR confirmed that the type II TGF-beta1 receptor mRNA is reduced in lesion cells. Transfection of the type II receptor into lesion cells restores the growth inhibitory response to TGF-beta1, implying that signaling remains responsive. Because TGF-beta1 is overexpressed in fibroproliferative vascular lesions, receptor-variant cells would be allowed to grow in a slow, but uncontrolled fashion, while overproducing extracellular matrix components. This TGF-beta1 receptor dysfunction may be relevant for atherosclerosis, restenosis and related fibroproliferative diseases.

Topics: Actins; Arteriosclerosis; Base Sequence; beta-Galactosidase; Cell Division; Coronary Disease; Coronary Vessels; DNA Primers; Extracellular Matrix Proteins; Gene Expression; Humans; Molecular Sequence Data; Muscle, Smooth, Vascular; Plasminogen Activator Inhibitor 1; Polymerase Chain Reaction; Protein Serine-Threonine Kinases; Proteoglycans; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Recombinant Proteins; Reference Values; RNA, Messenger; Transfection; Transforming Growth Factor beta

The objective of this investigation was to determine the effect of transforming growth factor beta 1 (TGF-beta 1) on endothelium-dependent relaxation in isolated epicardial coronary artery rings obtained from anesthetized dogs after multiple brief episodes of coronary artery occlusion and reperfusion in vivo. Dogs were subjected to four 5-minute periods of left anterior descending coronary artery occlusion interspersed with 5 minutes of reperfusion and followed by a final 1-hour period of reperfusion. Normal left circumflex coronary arteries were used as control samples. Repetitive ischemia and reperfusion significantly (p < 0.01) inhibited the relaxation response to acetylcholine in rings preconstricted with potassium. In an additional group of dogs subjected to the same protocol, 10 micrograms of human recombinant TGF-beta 1 was infused into the left anterior descending coronary artery distal to the site of occlusion via a diagonal branch at 0.3 ml/min immediately before and during the repetitive occlusions and reperfusions. TGF-beta 1 prevented impaired endothelium-dependent relaxation after multiple brief occlusions and reperfusions. These results demonstrate a protective role for TGF-beta 1 in the endothelial injury that occurs during repeated episodes of coronary artery occlusion and reperfusion.

Topics: Acetylcholine; Animals; Coronary Circulation; Coronary Disease; Coronary Vessels; Dogs; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Male; Myocardial Reperfusion; Myocardial Stunning; Recombinant Proteins; Recurrence; Time Factors; Transforming Growth Factor beta

To understand the complex mechanism(s) involved in molecular responses to ischemia, we developed two experimental models in pigs. In a "stunning" model of repetitive ischemia and reperfusion, we studied the mRNA expression of immediate early genes like c-fos, c-myc and heat shock protein-70 (HSP-70). Myocardial stunning was achieved by two cycles of 10-min left anterior descending coronary artery (LAD) occlusion and 30 min reperfusion. We observed several-fold enhanced expression of c-fos and HSP-70 mRNA in the stunned myocardium as compared with the control, whereas c-myc mRNA levels remained almost unchanged. In the second model, we examined the expression of the peptide mitogens heparin-binding growth factor 1 (HBGF-1) and transforming growth factor beta 1 (TGF-beta 1) after a chronic coronary artery occlusion leading to myocardial collateralization. Progredient stenosis of the circumflex coronary artery was induced by implanting a hygroscopic ameroid constrictor ring around it and occlusion was verified by in vivo angiography. Using polymerase chain reaction (PCR) and Northern hybridization techniques, we observed significantly enhanced expression of HBGF-1 and TGF-beta 1 in collateralized myocardium as compared with normal. In situ techniques revealed the localization of HBGF-1 transcripts in the blood vessel wall, and TGF-beta 1 in cardiac myocytes and Purkinje cells. Our results clearly indicate that myocardial stunning stimulates the expression of transcription factors which might be involved in regulation of certain growth factors like HBGF-1 and TGF-beta 1 which may play a significant role in the development of a collateral circulation.

Topics: Animals; Blotting, Northern; Coronary Disease; Coronary Vessels; Disease Models, Animal; Fibroblast Growth Factor 1; Gene Expression; Genes, fos; Genes, myc; Heat-Shock Proteins; Male; Myocardial Reperfusion; Myocardium; Neovascularization, Pathologic; Polymerase Chain Reaction; RNA, Messenger; Swine; Transcription, Genetic; Transforming Growth Factor beta

We investigated the expression of transforming growth factor beta 1 (TGF-beta 1), a polypeptide differentiation factor probably associated with angiogenic properties in chronically hypoperfused heart tissue. A slowly swelling ameroid constrictor was implanted around the coronary circumflex artery (CX) of young domestic pigs. Two to three weeks after, significant CX stenosis of more than 90% and coronary collateralization could be demonstrated angiographically. The CX dependent experimental myocardial tissue (E) was investigated, with the LAD dependent area of the same pig serving as a control (C). We found significantly enhanced TGF-beta 1 mRNA expression by northern blot hybridization in the experimental myocardium (E) of those pigs with demonstrable coronary collaterals in the absence of a major myocardial infarction. The presence of TGF-beta 1 protein could be demonstrated quantitatively in extracts of the experimental and the control area by immunoblot analysis. By in situ techniques, TGF-beta 1 mRNA and protein could be localized predominantly in cardiac myocytes. We conclude that one adaptive mechanism of the pig heart in chronic coronary artery constriction is the enhanced expression of TGF-beta 1. Cardiac myocytes are a major source of TGF-beta 1. The observed coronary collateralization could be mediated-at least in part-by the angiogenic properties of TGF-beta 1.

Topics: Adaptation, Biological; Animals; Arteries; Blotting, Northern; Blotting, Western; Coronary Angiography; Coronary Circulation; Coronary Disease; Fluorescent Antibody Technique; Gene Expression; Male; Nucleic Acid Hybridization; Purkinje Fibers; RNA, Messenger; Swine; Transforming Growth Factor beta