transforming-growth-factor-beta and Metabolic-Syndrome

Chymase plays a crucial role in angiotensin II formation in various tissues. Angiotensin II induces gene expressions of transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-9, and chymase also converts precursors of TGF-β and MMP-9 to their active forms. All of angiotensin II, TGF-β and MMP-9 are considered to be closely involved in the development and progression of metabolic syndrome and its complications. In a diabetic animal model, chymase induced pancreatic disorganization via attack of oxidative stress induced by augmentation of chymase-forming angiotensin II. In atherosclerotic lesions in patients, accumulation of chymase-positive cells was observed, and chymase inhibition prevented the development of atherosclerosis in an animal model. In Apo E-deficient mice, chymase inhibition prevents the development of angiotensin II-induced abdominal aneurysmal aorta (AAA). In this model, the AAA development on an increase in MMP-9 activities induced by angiotensin II, but the inhibition of MMP-9 activation by chymase inhibitor resulted in attenuation of the AAA development. Cardiac dysfunction after myocardial infarction was also attenuated by chymase inhibition. Steatosis and fiblosis in liver were strongly prevented by chymase inhibition in an animal model with nonalcoholic steatohepatitis which is involved in metabolic syndrome. Therefore, chymase inhibition may be useful for attenuating MMP-9 and TGF-β levels, in addition to reducing angiotensin II formation, and this function may provide powerful preventions of organ damages. In this review, we propose the significance of chymase as a target to prevent complications of metabolic syndrome.

Topics: Angiotensin II; Animals; Atherosclerosis; Chymases; Diabetes Complications; Diabetic Retinopathy; Fatty Liver; Humans; Hypertension; Matrix Metalloproteinase 9; Metabolic Syndrome; Mice; Transforming Growth Factor beta

Activation of thermogenic brown and beige adipocytes is considered as a strategy to improve metabolic control. Here, we identify GPR180 as a receptor regulating brown and beige adipocyte function and whole-body glucose homeostasis, whose expression in humans is associated with improved metabolic control. We demonstrate that GPR180 is not a GPCR but a component of the TGFβ signalling pathway and regulates the activity of the TGFβ receptor complex through SMAD3 phosphorylation. In addition, using genetic and pharmacological tools, we provide evidence that GPR180 is required to manifest Collagen triple helix repeat containing 1 (CTHRC1) action to regulate brown and beige adipocyte activity and glucose homeostasis. In this work, we show that CTHRC1/GPR180 signalling integrates into the TGFβ signalling as an alternative axis to fine-tune and achieve low-grade activation of the pathway to prevent pathophysiological response while contributing to control of glucose and energy metabolism.

Topics: Adipocytes, Beige; Adipocytes, Brown; Animals; Energy Metabolism; Extracellular Matrix Proteins; Glucose; Homeostasis; Humans; Male; Metabolic Diseases; Metabolic Syndrome; Mice, Inbred C57BL; Mice, Knockout; Receptors, G-Protein-Coupled; Signal Transduction; Thermogenesis; Transforming Growth Factor beta

Coffee has been shown to attenuate sarcopenia, the age-associated muscle atrophy. Myostatin (MSTN), a member of the TGF-β growth/differentiation factor superfamily, is a potent negative regulator of skeletal muscle mass, and MSTN-inhibition increases muscle mass or prevents muscle atrophy. This study, thus, investigated the presence of MSTN-inhibitory capacity in coffee extracts. The ethanol-extract of coffee silverskin (CSE) but not other extracts demonstrated anti-MSTN activity in a pGL3-(CAGA)

Topics: Administration, Oral; Animals; Blood Glucose; Body Weight; Bone and Bones; Coffee; Ethanol; Fatty Acids, Nonesterified; Inhibitory Concentration 50; Male; Metabolic Syndrome; Mice; Mice, Inbred ICR; Muscle, Skeletal; Muscles; Myostatin; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; RNA, Messenger; Solvents; Transforming Growth Factor beta; Uncoupling Protein 1

Metabolic syndrome (MetS) profoundly changes the contents of mesenchymal stem cells and mesenchymal stem cells-derived extracellular vesicles (EVs). The anti-inflammatory TGF-β (transforming growth factor-β) is selectively enriched in EVs from Lean but not from MetS pigs, but the functional impact of this endowment remains unknown. We hypothesized that Lean-EVs more effectively induce regulatory T cells in injured kidneys. Five groups of pigs (n=7 each) were studied after 16 weeks of diet-induced MetS and unilateral renal artery stenosis (RAS; MetS+RAS). Two groups of MetS+RAS were treated 4 weeks earlier with an intrarenal injection of either Lean-EVs or MetS-EVs. MetS+RAS had lower renal volume, renal blood flow, and glomerular filtration rate than MetS pigs. Compared with Lean-EVs, MetS-EVs were less effective in improving renal function and decreasing tubular injury and fibrosis in MetS+RAS. Lean-EVs upregulated TGF-β expression in stenotic kidney and increased regulatory T cells numbers more prominently. Furthermore, markedly upregulated anti-inflammatory M2 macrophages reduced proinflammatory M1 macrophages, and CD8

Topics: Animals; Coculture Techniques; Cytokines; Dietary Carbohydrates; Dietary Fats; Extracellular Vesicles; Female; Inflammation; Infusions, Intra-Arterial; Metabolic Syndrome; MicroRNAs; Monocytes; Random Allocation; Renal Artery; Renal Artery Obstruction; Renal Circulation; Renal Insufficiency, Chronic; Signal Transduction; Swine; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

TGFβ is a key player in cartilage homeostasis and OA pathology. However, few data are available on the role of TGFβ signalling in the different OA phenotypes. Here, we analysed the TGFβ pathway by transcriptomic analysis in six mouse models of OA.. We have brought together seven expert laboratories in OA pathophysiology and, used inter-laboratories standard operating procedures and quality controls to increase experimental reproducibility and decrease bias. As none of the available OA models covers the complexity and heterogeneity of the human disease, we used six different murine models of knee OA: from post-traumatic/mechanical models (meniscectomy (MNX), MNX and hypergravity (HG-MNX), MNX and high fat diet (HF-MNX), MNX and seipin knock-out (SP-MNX)) to aging-related OA and inflammatory OA (collagenase-induced OA (CIOA)). Four controls (MNX-sham, young, SP-sham, CIOA-sham) were added. OsteoArthritis Research Society International (OARSI)-based scoring of femoral condyles and ribonucleic acid (RNA) extraction from tibial plateau samples were done by single operators as well as the transcriptomic analysis of the TGFβ family pathway by Custom TaqMan® Array Microfluidic Cards.. The transcriptomic analysis revealed specific gene signatures in each of the six models; however, no gene was deregulated in all six OA models. Of interest, we found that the combinatorial Gdf5-Cd36-Ltbp4 signature might discriminate distinct subgroups of OA: Cd36 upregulation is a hallmark of MNX-related OA while Gdf5 and Ltbp4 upregulation is related to MNX-induced OA and CIOA.. These findings stress the OA animal model heterogeneity and the need of caution when extrapolating results from one model to another.

Topics: Animals; Arthritis, Experimental; CD36 Antigens; Collagenases; Diet, High-Fat; Disease Models, Animal; Gene Expression Profiling; Growth Differentiation Factor 5; GTP-Binding Protein gamma Subunits; Hypergravity; Latent TGF-beta Binding Proteins; Meniscectomy; Metabolic Syndrome; Mice; Mice, Knockout; Obesity; Osteoarthritis; Transcriptome; Transforming Growth Factor beta

Psoriasis course involves increased secretion of pro-inflammatory cytokines, among others, a beta transforming growth factor (TGFβs) and its receptors. Cyclosporine A (CsA), an immunosuppressive medicine with the molecular mechanism of operation connected with the properties of cell cycle suppression, is often used in the treatment of severe forms of psoriasis. The efficacy of therapy is assessed based on the disease clinical progression indexes - Psoriasis Area and Severity Index (PASI), body surface area (BSA), and Dermatology Life Quality Index (DLQI). The aim of the study was the evaluation of the efficacy of the CsA treatment of patients with psoriasis vulgaris, based on the clinical parameters and an assessment of the expression profiles of TGFβs and TGFβRs, depending on the concurrent diabetes and metabolic syndrome.. The group under study composed of 32 patients (15 with the metabolic syndrome, seven with diabetes) treated with CsA for 84 days. The molecular analysis included extraction of RNA, assessment of TGβF1-3, TGFβRI-III gene expression with the use of the RTqPCR method. The clinical assessment of the effects of this pharmacotherapy involved evaluation of the parameters: PASI, BSA, DLQI before therapy commencement, on the 42nd and 84th days of therapy.. A statistically significant change in the transcription activity of TGFβ1 in patients with and without diabetes (P = 0.018) and patients with and without metabolic syndrome (P = 0.023) was shown that on the 84th day of therapy.. TGFb1 may be claimed as the supplementary molecular marker to evaluate the efficacy of CsA therapy. It seems that systemic diseases have an effect on the efficacy of the applied pharmacotherapy and the course of psoriasis.

Topics: Cyclosporine; Diabetes Complications; Female; Gene Expression; Humans; Immunosuppressive Agents; Male; Metabolic Syndrome; Proteoglycans; Psoriasis; Quality of Life; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; RNA, Messenger; Severity of Illness Index; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Transforming Growth Factor beta3; Treatment Outcome

Nonalcoholic steatohepatitis (NASH), in which there is steatosis and fibrosis in the liver, is linked to metabolic syndrome and progresses to hepatic cirrhosis. In this study, a novel hamster NASH model derived from metabolic syndrome was made using hamsters. Hamsters were fed a normal or a high-fat and high-cholesterol (HFC) diet for 12 weeks. Body weight and the ratio of liver weight to body weight were significantly greater in HFC diet-fed hamsters than in normal diet-fed hamsters. Triglyceride, low-density lipoprotein cholesterol, and glucose levels in blood were significantly increased in HFC diet-fed hamsters, and blood pressure also tended to be high, suggesting that the HFC diet-fed hamsters developed metabolic syndrome. Hepatic steatosis and fibrosis were observed in liver sections of HFC diet-fed hamsters, as in patients with NASH, but they were not seen in normal diet-fed hamsters. Chymase generates angiotensin II and transforming growth factor (TGF)-β, both of which are related to hepatic steatosis and fibrosis, and a significant augmentation of chymase activity was observed in livers from HFC diet-fed hamsters. Both angiotensin II and TGF-β were also significantly increased in livers of HFC diet-fed hamsters. Thus, HFC diet-fed hamsters might develop metabolic syndrome-derived NASH that clinically resembles that in NASH patients.

Topics: Angiotensin II; Animals; Body Weight; Cholesterol, Dietary; Chymases; Cricetinae; Diet, High-Fat; Disease Models, Animal; Liver; Liver Cirrhosis; Male; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Organ Size; Transforming Growth Factor beta

Molecular- and cellular-based therapies have the potential to reduce obesity-associated disease. In response to cold, beige adipocytes form in subcutaneous white adipose tissue and convert energy stored in metabolic substrates to heat, making them an attractive therapeutic target. We developed a robust method to generate a renewable source of human beige adipocytes from induced pluripotent stem cells (iPSCs). Developmentally, these cells are derived from FOXF1

Topics: Adipocytes, Beige; Cell Differentiation; Cell Line; Forkhead Transcription Factors; Humans; Induced Pluripotent Stem Cells; Interleukin-4; Mesenchymal Stem Cells; Mesoderm; Metabolic Syndrome; Signal Transduction; Splanchnic Circulation; Transforming Growth Factor beta

Obesity and its associated complications such as insulin resistance and non-alcoholic fatty liver disease are reaching epidemic proportions. In mice, the TGF-β superfamily is implicated in the regulation of white and brown adipose tissue differentiation. The kielin/chordin-like protein (KCP) is a secreted regulator of the TGF-β superfamily pathways that can inhibit both TGF-β and activin signals while enhancing bone morphogenetic protein (BMP) signaling. However, KCP's effects on metabolism and obesity have not been studied in animal models. Therefore, we examined the effects of KCP loss or gain of function in mice that were maintained on either a regular or a high-fat diet. KCP loss sensitized the mice to obesity and associated complications such as glucose intolerance and adipose tissue inflammation and fibrosis. In contrast, transgenic mice that expressed KCP in the kidney, liver, and adipose tissues were resistant to developing high-fat diet-induced obesity and had significantly reduced white adipose tissue. Moreover, KCP overexpression shifted the pattern of SMAD signaling

Topics: Adipocytes; Animals; Bone Morphogenetic Protein 7; Carrier Proteins; Dietary Fats; Metabolic Syndrome; Mice; Mice, Knockout; Obesity; Organ Specificity; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

The transforming growth factor-β (TGF-β) signaling pathway and its relevant genes have been correlated with an increased risk of developing various hallmarks of metabolic syndrome (MetS). In this study, we assessed whether the TGF-β signaling pathway-associated genes of SMAD family member 2 (SMAD2), SMAD3, SMAD4, transforming growth factor beta 1 (TGFB1), TGFB2, TGFB3, transforming growth factor beta receptor 1 (TGFBR1), and TGFBR2 are associated with MetS and its individual components independently, through complex interactions, or both in a Taiwanese population. A total of 3,000 Taiwanese subjects from the Taiwan Biobank were assessed. Metabolic traits such as waist circumference, triglyceride, high-density lipoprotein cholesterol, systolic and diastolic blood pressure, and fasting glucose were measured. Our results showed a significant association of MetS with the two single nucleotide polymorphisms (SNPs) of SMAD2 rs11082639 and TGFBR2 rs3773651. The association of MetS with these SNPs remained significant after performing Bonferroni correction. Moreover, we identified the effect of SMAD2 rs11082639 on high waist circumference. We also found that an interaction between the SMAD2 rs11082639 and TGFBR2 rs3773651 SNPs influenced MetS. Our findings indicated that the TGF-β signaling pathway-associated genes of SMAD2 and TGFBR2 may contribute to the risk of MetS independently and through gene-gene interactions.

Topics: Adult; Asian People; Female; Genetic Predisposition to Disease; Humans; Male; Metabolic Syndrome; Middle Aged; Polymorphism, Single Nucleotide; Receptor, Transforming Growth Factor-beta Type II; Signal Transduction; Smad2 Protein; Taiwan; Transforming Growth Factor beta

The purpose of the study was to develop a novel diet based on standard AIN93G diet that would be able to induce experimental obesity and impair immune regulation with high concentrations of both carbohydrate and lipids.. To compare the effects of this high sugar and butter (HSB) diet with other modified diets, male C57BL/6 mice were fed either mouse chow, or AIN93G diet, or high sugar (HS) diet, or high-fat (HF) diet, or high sugar and butter (HSB) diet for 11 weeks ad libitum. HSB diet induced higher weight gain. Therefore, control AIN93G and HSB groups were chosen for additional analysis. Regulatory T cells were studied by flow cytometry, and cytokine levels were measured by ELISA.. Although HF and HSB diets were able to induce a higher weight gain compatible with obesity in treated mice, HSB-fed mice presented the higher levels of serum glucose after fasting and the lowest frequency of regulatory T cells in adipose tissue. In addition, mice that were fed HSB diet presented higher levels of cholesterol and triglycerides, hyperleptinemia, increased resistin and leptin levels as well as reduced adiponectin serum levels. Importantly, we found increased frequency of CD4(+)CD44(+) effector T cells, reduction of CD4(+)CD25(+)Foxp3(+) and Th3 regulatory T cells as well as decreased levels of IL-10 and TGF-β in adipose tissue of HSB-fed mice.. Therefore, HSB represents a novel model of obesity-inducing diet that was efficient in triggering alterations compatible with metabolic syndrome as well as impairment in immune regulatory parameters.

Topics: Adipokines; Adipose Tissue; Animals; Blood Glucose; Cholesterol; Diet, High-Fat; Dietary Carbohydrates; Dietary Fats; Interleukin-10; Male; Metabolic Syndrome; Mice, Transgenic; Obesity; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Triglycerides

Metabolic syndrome is associated with pathological remodeling of the heart and adjacent vessels. The early biochemical and cellular changes underlying the vascular damage are not fully understood. In this study, we sought to establish the nature, extent, and initial timeline of cytochemical derangements underlying reduced ventriculo-arterial compliance in a swine model of metabolic syndrome.. Yorkshire swine (n = 8 per group) were fed a normal diet (ND) or a high-cholesterol (HCD) for 12 weeks. Myocardial function and blood flow was assessed before harvesting the heart. Immuno-blotting and immuno-histochemical staining were used to assess the cellular changes in the myocardium, ascending aorta and left anterior descending artery (LAD).. There was significant increase in body mass index, blood glucose and mean arterial pressures (p = 0.002, p = 0.001 and p = 0.024 respectively) in HCD group. At the cellular level there was significant increase in anti-apoptotic factors p-Akt (p = 0.007 and p = 0.002) and Bcl-xL (p = 0.05 and p = 0.01) in the HCD aorta and myocardium, respectively. Pro-fibrotic markers TGF-β (p = 0.01), pSmad1/5 (p = 0.03) and MMP-9 (p = 0.005) were significantly increased in the HCD aorta. The levels of pro-apoptotic p38MAPK, Apaf-1 and cleaved Caspase3 were significantly increased in aorta of HCD (p = 0.03, p = 0.04 and p = 0.007 respectively). Similar changes in coronary arteries were not observed in either group. Functionally, the high cholesterol diet resulted in significant increase in ventricular end systolic pressure and-dp/dt (p = 0.05 and p = 0.007 respectively) in the HCD group.. Preclinical metabolic syndrome initiates pro-apoptosis and pro-fibrosis pathways in the heart and ascending aorta, while sparing coronary arteries at this early stage of dietary modification.

Topics: Animals; Aorta; Apoptosis; Apoptotic Protease-Activating Factor 1; Caspase 3; Diet, High-Fat; Fibrosis; Metabolic Syndrome; Myocardium; p38 Mitogen-Activated Protein Kinases; Smad1 Protein; Swine; Transforming Growth Factor beta

The prevalence of metabolic syndrome persistently increases and affects over 30% of U.S. adults. To study how metabolic syndrome may induce tubulointerstitial injury and whether acetaminophen has renal-protective properties, 4-week-old obese Zucker rats were randomly assigned into three groups, control (OC), vehicle dimethyl sulfoxide (OV), and acetaminophen treatment (30 mg/kg/day for 26 weeks), and lean Zucker rats served as healthy controls. Significant tubulointerstitial injuries were observed in both OC and OV animals, evidenced by increased tubular cell death, tubular atrophy/dilation, inflammatory cell infiltration, and fibrosis. These tubulointerstitial alterations were significantly reduced by treatment with a chronic but low dose of acetaminophen, which acted to diminish NADPH oxidase isoforms Nox2 and Nox4 and decrease tubulointerstitial oxidative stress (reduced tissue superoxide and macromolecular oxidation). Decreased oxidative stress by acetaminophen was paralleled by the reduction of tubular proapoptotic signaling (diminished Bax/Bcl-2 ratio and caspase 3 activation) and the alleviation of tubular epithelial-to-mesenchymal transition (decreased transforming growth factor β, connective tissue growth factor, α-smooth muscle actin, and laminin). These data suggest that increased oxidative stress plays a critical role in mediating metabolic syndrome-induced tubulointerstitial injury and provide the first evidence suggesting that acetaminophen may be of therapeutic benefit for the prevention of tubulointerstitial injury.

Topics: Acetaminophen; Actins; Analgesics, Non-Narcotic; Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Connective Tissue Growth Factor; Epithelial-Mesenchymal Transition; Fibrosis; Gene Expression; Inflammation; Kidney Tubules; Laminin; Male; Membrane Glycoproteins; Metabolic Syndrome; NADPH Oxidase 2; NADPH Oxidase 4; NADPH Oxidases; Nephritis, Interstitial; Oxidative Stress; Rats; Rats, Zucker; Transforming Growth Factor beta

The seriousness of metabolic syndrome is not due to the disease itself but its promotion of other diseases, such as erectile dysfunction and cardiovascular and cerebrovascular diseases. We investigated the effects of Korean red ginseng (KRG, Panax ginseng) extract on erectile function in a rat model of metabolic syndrome. We divided the rats into three groups: control, metabolic syndrome+normal saline (N/S) and metabolic syndrome+KRG. To determine the occurrence of metabolic syndrome in all groups, body weight and various biochemical parameters (e.g., blood glucose, insulin, cholesterol) were measured, and the intra-abdominal glucose tolerance test was performed. To investigate penile erection, the peak intracavernosal pressure (ICP), mean arterial pressure (MAP) and Masson's trichrome stain were evaluated. Erectile function was also investigated by measuring the cyclic guanosine monophosphate (cGMP) levels of the corpus cavernosum. We found that the various biochemical parameters and body weight were similar in the metabolic syndrome+KRG group and the control group, although the values were slightly higher. The peak ICP/MAP ratio of the metabolic syndrome+N/S group was markedly decreased compared to the other groups. The cGMP level of the corpus cavernosum in the metabolic syndrome+N/S group was significantly lower than that of the other groups. As demonstrated in this model of metabolic syndrome with erectile dysfunction, KRG may improve erectile function.

Topics: Animals; Arterial Pressure; Cyclic GMP; Disease Models, Animal; Erectile Dysfunction; Male; Metabolic Syndrome; Panax; Penile Erection; Penis; Phytotherapy; Plant Extracts; Rats; Rats, Inbred WKY; Transforming Growth Factor beta

Recent research implies a role of decreased number and/or function of T-regulatory cells (Tregs) in low-grade inflammation associated with obesity and atherosclerosis. The enhancement of atheroprotective immunity by the expansion of Tregs could serve as a therapeutic strategy in obesity-related immunological disturbances. The aim of our study was an attempt to generate Treg cells in children with risk factors for the development of cardiovascular disease and to compare the results to those obtained in healthy subjects. The study group consisted of 30 children with metabolic syndrome (MS) and 30 controls. Conventional CD4(+)CD25(-) cells separated from the peripheral blood were converted into Treg cells with the use of CD3/CD28 antibodies and interleukin (IL)-2/transforming growth factor (TGF)-β stimulation. The expression of critical Treg molecules and cytokines was assessed at mRNA and protein levels. The percentages of Treg cells in the peripheral blood were significantly lower in the children with MS compared to the healthy subjects. After the culture with CD3/CD28 and IL-2/TGF-β we detected a significant increase in the expression of Tregs marker transcription factor FoxP3. The Tregs induced from the children with MS varied from the ones obtained in the controls in the expression of some molecules at mRNA level (e.g. IL-27, LGAL, KLF10 and NRP1) yet not in proliferation studies. For the first time, we have demonstrated the possibility of generating functional Treg cells in children with MS. The results of our study could be used in the design of therapeutic interventions in obesity associated immunologic disturbances.

Topics: Adolescent; Age Factors; Antibodies; Case-Control Studies; CD28 Antigens; CD3 Complex; Cell Proliferation; Cells, Cultured; Female; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Interleukin-2; Lymphocyte Activation; Male; Metabolic Syndrome; Obesity; RNA, Messenger; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

The term metabolic syndrome (MS) refers to a conglomeration of many metabolic disorders. Recent studies suggest that inflammation plays a vital role in MS. There are however no data available on the recently characterized novel T-cell-derived cytokine interleukin (IL)-17 in MS; studies on the anti-inflammatory cytokine transforming growth factor (TGF)-β are also limited. The aim of the study was to look at IL-17 and TGF-β levels in subjects with and without MS. The study subjects were recruited from the Chennai Urban Rural Epidemiology Study (CURES), a population-based study in Chennai (formerly Madras) in southern India. Group 1 consisted of subjects without MS (non-MS) (n = 98) and group 2 consisted of subjects with MS (n = 156). MS was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria modified for waist, according to the World Health Organization Asia Pacific guidelines. Serum IL-17 and TGF-β levels were estimated by enzyme-linked immunosorbent assay. Interleukin-17 levels were decreased (P < .001) and TGF-β levels (P < .001) were increased in subjects with MS compared to those without. With an increase in the number of metabolic risk factors, the IL-17 levels showed a decline, whereas the TGF-β levels showed an increase (P < .001). With respect to individual components of MS, TGF-β and IL-17 showed a significant association with blood pressure and blood glucose even after adjusting for age and sex. We report that IL-17 levels are decreased, whereas TGF-β levels are increased, among Asian Indians with MS.

Topics: Adult; Anthropometry; Blood Glucose; Cholesterol; Cholesterol, HDL; Female; Humans; India; Interleukin-17; Logistic Models; Male; Metabolic Syndrome; Middle Aged; Rural Population; Transforming Growth Factor beta; Triglycerides

Non-alcoholic steatohepatitis (NASH), which is a common liver disease in industrialized countries, is associated with obesity, hypertension, and type-2 diabetes (metabolic syndrome). Since angiotensin II (ANG II) has been suggested to play an important role in liver inflammation and fibrosis, the purpose of this study was to investigate whether therapy against renin-angiotensin system (RAS) may provide some beneficial effect in liver of an animal model of metabolic syndrome.. For 6 months, obese Zucker rats (OZRs) were treated as follows: OZR-group, OZR + Perindopril (P) group, OZR + Irbesartan (IRB) group, OZR + Amlodipine (AML) group, and lean Zucker rats (LZRs) group as a control. Livers were evaluated by immunohistochemistry techniques using corresponding antibodies.. All treated groups showed a similar reduction in blood pressure compared to untreated OZR. Therapy either with IRB or P improves insulin sensitivity and reduces hepatic enzyme level with respect to untreated OZR. Conversely, AML failed to modify both parameters. Untreated OZR displayed higher hepatic ANG II levels and steatosis together with a marked increase in tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and transforming growth factor-beta1 (TGF-beta1) level compared to LZR. Following RAS inhibition either by P or IRB, a significant reduction (P < 0.01) in the immunostaining of TNF-alpha, IL-6 and TGF-beta1 compared to untreated OZR was observed.. These results indicate that ANG II expression is increased in the liver of these animals with steatohepatitis. Furthermore, RAS control by either angiotensin-converting enzyme inhibition or AT1 receptor blockade seems to provide a beneficial modulation concerning the inflammatory response to liver injury in this model. Consequently, blockade of RAS could be a new approach to prevent or to treat patients with NASH.

Topics: Amlodipine; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Biphenyl Compounds; Disease Models, Animal; Fatty Liver; Interleukin-6; Irbesartan; Liver; Liver Cirrhosis; Male; Metabolic Syndrome; Obesity; Perindopril; Rats; Rats, Zucker; Renin-Angiotensin System; Tetrazoles; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The metabolic syndrome (MS) is associated with left ventricular hypertrophy (LVH). Previous evidence has shown that LVH is favoured by low levels of atrial natriuretic peptide (ANP), independently from blood pressure (BP), in hypertension. Although levels of natriuretic peptides are known to be lower in obesity, plasma ANP levels have not yet been assessed in MS. We aimed to assess the ANP levels and their relationship with left ventricular mass (LVM) in patients affected by MS.. One hundred and twenty-eight essential hypertensive patients were included in the study: 51 with MS and 77 without MS. Clinical, echocardiographical and biochemical parameters, and levels of both N-terminal (NT)-proANP and alphaANP were assessed.. Hypertensive patients affected by MS had higher LVM and increased frequency of LVH. NT-proANP levels were significantly lower in MS, independent of waist circumference (WC). Log(NT-proANP) levels were significantly inversely related to left ventricular mass index (LVMI) (beta = -0.360, P < 0.001) and LVM/height (beta = -0.370, P < 0.001) in the whole hypertensive population by multiple linear regression analysis. The relationship of log(NT-proANP) with LVM was more enhanced in patients with MS.. The present study demonstrates that levels of NT-proANP are significantly reduced in hypertensive patients affected by MS, and they are significantly inversely related to the increased LVM observed in these patients. Our findings, while supporting previous experimental and clinical evidence of the antihypertrophic role of ANP in hypertension, may help to identify one of the possible mechanisms directly underlying LVH in MS.

Topics: Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Case-Control Studies; Echocardiography, Doppler; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Linear Models; Male; Metabolic Syndrome; Middle Aged; Predictive Value of Tests; Protein Precursors; Rome; Stroke Volume; Transforming Growth Factor beta

Previous studies have shown that metabolic syndrome (MS) is associated with an increased susceptibility to develop cardiovascular damage (CD). Experimental evidence indicates that inflammation and fibrosis could play a critical role in the development of CD in hypertension. This issue has not been clarified yet in patients with MS. The aim of our study was to investigate the relationship between markers of inflammation and fibrosis with CD in hypertensive patients with and without MS.. One hundred twenty-eight essential hypertensive patients were included in the study: 51 with MS and 77 without MS. Clinical, biochemical parameters, 24-h urinary albumin excretion rate (UAER), levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), and procollagen type 1 carboxy-terminal propeptide (PICP) were measured. All patients underwent an echocardiographic examination with transmitral Doppler and tissue Doppler imaging (TDI).. Left ventricular mass indexed by height(2.7) (LVM/h(2.7)) (P < .001), early diastolic peak flow velocity/early myocardial diastolic velocity ratio (E/Em ratio), a TDI index of diastolic function (P < .001), and 24-h UAER (P < .05) were significantly higher in the group with MS, whereas peak myocardial systolic velocity (Sm), a TDI index of systolic function (P < .001), was lower. Serum levels of CRP (P < .001), TNF-alpha (P < .05), TGF-beta (P < .01), and PICP (P < .001) were significantly increased in MS. These markers were significantly related to higher LVMI(2.7), higher E/Em ratio, and increased 24-h UAER and a lower Sm in the whole population, with a further significant enhancement in MS.. Cardiovascular damage is more frequent in hypertensives with MS than in hypertensives without MS, and this is significantly related to the increased levels of inflammation and fibrosis found in hypertensives with MS.

Topics: Albuminuria; Biomarkers; Blood Pressure; C-Reactive Protein; Cardiovascular Diseases; Case-Control Studies; Diastole; Female; Fibrosis; Humans; Hypertension; Hypertrophy, Left Ventricular; Inflammation; Male; Metabolic Syndrome; Middle Aged; Peptide Fragments; Procollagen; Systole; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

To determine whether angiotensin converting enzyme inhibition by perindopril can reduce cardiac transforming growth factor beta1 (TGFbeta1) and plasminogen activator inhibitor 1 (PAI-1) and therefore control collagen accumulation in an animal model with the metabolic syndrome such as the obese Zucker rat (OZR).. Male OZR (group 1, n = 10); OZR treated with perindopril (group 2, n = 10); and lean Zucker rats (group 3, n = 10).. During six months, group 2 received 3 mg/kg/day of perindopril orally and group 1 and group 3 were given a vehicle. Hearts were processed for pathology studies including immunohistochemical analysis with antibodies to PAI-1, TGFbeta1, collagen type I, and collagen type III.. Group 2 had lower blood pressure (126.7 (2) v 148.6 (2.7) mm Hg, p < 0.01) than untreated OZR and had decreased cardiac PAI-1 (3.6 (0.4) v 13.5 (1.7)% of positive area/field, p < 0.01), TGFbeta1 in myocytes (0.13 (0.1) v 9.14 (4.7)%/area, p < 0.01) and in interstitium (19.8 (6.8) v 178.9 (27.4) positive cells/area, p < 0.01), collagen I (3 (0.8) v 13.3 (1)%/area, p < 0.01), collagen III (5 (0.6) v 9.5 (0.9)%/area, p < 0.01), and collagen I to collagen III ratio (0.59 (0.13) v 1.40 (0.15) p < 0.01) compared with untreated OZR.. These results suggest that perindopril reduces cardiac PAI-1 and TGFbeta1 and ameliorates cardiac fibrosis in a rat model with multiple cardiovascular risk factors.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Collagen; Disease Models, Animal; Male; Metabolic Syndrome; Myocardium; Obesity; Organ Size; Perindopril; Plasminogen Activator Inhibitor 1; Rats; Rats, Zucker; Transforming Growth Factor beta; Transforming Growth Factor beta1

LDL receptor (LDLR)-null mice fed high-fat/cholesterol diets, a model of the metabolic syndrome, have vascular calcification (VC) worsened by chronic kidney disease (CKD) and ameliorated by bone morphogenetic protein-7 (BMP-7), an efficacious agent in treating animal models of renal osteodystrophy. Here, LDLR-/- high-fat-fed mice without CKD were shown to have significant reductions in bone formation rates, associated with increased VC and hyperphosphatemia. Superimposing CKD resulted in a low turnover osteodystrophy, whereas VC worsened and hyperphosphatemia persisted. BMP-7 treatment corrected the hyperphosphatemia, corrected the osteodystrophy, and prevented VC, compatible with skeletal phosphate deposition leading to reduced plasma phosphate and removal of a major stimulus to VC. A pathologic link between abnormal bone mineralization and VC through the serum phosphorus was supported by the partial effectiveness of directly reducing the serum phosphate by a phosphate binder that had no skeletal action. Thus, in this model of the metabolic syndrome with CKD, a reduction in bone-forming potential of osteogenic cells leads to low bone turnover rates, producing hyperphosphatemia and VC, processes ameliorated by the skeletal anabolic agent BMP-7, in part through deposition of phosphate and increased bone formation.

Topics: Animals; Aorta; Aortic Diseases; Bone and Bones; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Remodeling; Calcinosis; Calcium; Chronic Disease; Chronic Kidney Disease-Mineral and Bone Disorder; Dietary Fats; Dose-Response Relationship, Drug; Female; Kidney Diseases; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Parathyroid Glands; Phosphates; Receptors, LDL; Transforming Growth Factor beta

An increase in fat mass associated with obesity results from recruitment and differentiation of adipocyte progenitor cells. The precise origin of these cells is unknown, although accumulating evidence suggests that circulating stem cells can differentiate into cells of mesenchymal lineage. It is currently unclear whether a progenitor adipocyte population exists in circulation. One potential candidate is the fibrocyte, which may represent a common progenitor cell for several mesenchymal lineages. We demonstrate that these circulating progenitors become adipocytes when cultured under adipogenic conditions, with intracellular lipids accumulation and up-regulation of proteins specific for adipocyte differentiation, including leptin, PPARgamma, and FABP4. cDNA microarray analysis revealed gene clusters that were differentially regulated during adipogenesis of fibrocytes, which were similar to visceral and subcutaneous adipose tissue preadipocyte-to-adipocyte differentiation. Moreover, these progenitors engrafted and formed human adipose tissue following injection into SCID mice. Although fibrocytes express an array of chemokine receptors, we observed an up-regulation of CCR2 expression following fibrocytes differentiation into adipocytes, which was associated with increased chemotactic response to CCL2. This paradigm supports the notion that elevated CCL2 levels in visceral adipose tissue associated with Metabolic Syndrome is a chemotactic niche, whereby fibrocytes can home to and differentiate into adipocytes to perpetuate its tissue formation.

Topics: Adipocytes; Adipose Tissue; Animals; Cell Differentiation; Cell Lineage; Chemokine CCL2; Chemokines; DNA, Complementary; Gene Expression Regulation; Genome; Humans; Lipids; Mesoderm; Metabolic Syndrome; Mice; Mice, SCID; Models, Biological; Multigene Family; Oligonucleotide Array Sequence Analysis; Software; Stem Cells; Transforming Growth Factor beta; Up-Regulation

In this study, we evaluated whether a combination of an angiotensin-converting enzyme (ACE) inhibitor, benazepril (B), with an angiotensin type I receptor antagonist (AT1RA), irbesartan (I), is as effective or more than drugs as monotherapy in controlling renal damage in obese Zucker rats (OZR), a model of metabolic syndrome.. During six months, G1 (OZR receiving no treatment); G2 (OZR with B 10 mg/kg/day); G3 (OZR with I 50mg/kg/day); and G4 (OZR with B 5mg/kg/day + I 25 mg/kg/day). Kidneys were processed for light microscopy (LM) and immunohistochemistry, including antibodies against interstitial alpha-smooth-muscle-actin (alpha-SMA), plasminogen activator inhibitor-1 (PAI-1), transforming growth factor-beta(1)(TGF-beta 1), and collagen (COL) I, III, and IV.. All treated groups presented similar reduction in blood pressure compared with untreated OZR. However, animals from G4 (B + I) showed better control on proteinuria together with a higher creatinine clearance. Additionally, G4 showed a significant (P < 0.05) lower kidney weight; smaller glomerular area; lower glomerulosclerosis score; lower percentage of tubular atrophy, interstitial fibrosis, and interstitial alpha-SMA; lower tubular PAI-1 score; lower percentage of COL I, III, and IV in renal interstitium; and lower wall/lumen ratio in renal vessels, when compared with the other groups. OZR treated with B and/or I showed a better outcome (P < 0.01) in the carbohydrate and lipid metabolism in comparison with untreated OZR.. These results suggest that combined therapy using B and I is more effective than therapy with either drug at monotherapy for controlling renal damage in this animal model. In addition, data presented here reaffirm the benefit of interacting against renin-angiotensin-system (RAS) in the metabolic syndrome.

Topics: Actins; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Biphenyl Compounds; Collagen; Drug Therapy, Combination; Irbesartan; Kidney; Male; Metabolic Syndrome; Obesity; Organ Size; Plasminogen Activator Inhibitor 1; Rats; Rats, Zucker; Tetrazoles; Transforming Growth Factor beta; Transforming Growth Factor beta1