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Type-2 diabetes-induced changes in vascular extracellular matrix gene expression: relation to vessel size.

ABSTRACT: Hyperglycemia-induced changes in vascular wall structure contribute to the pathogenesis of diabetic microvascular and macrovascular complications. Matrix metalloproteinases (MMP), a family of proteolytic enzymes that degrade extracellular matrix (ECM) proteins, are essential for vascular remodeling. We have shown that endothelin-1 (ET-1) mediates increased MMP activity and associated vascular remodeling in Type 2 diabetes. However, the effect of Type 2 diabetes and/or ET-1 on the regulation of ECM and MMP gene expression in different vascular beds remains unknown.Aorta and mesenteric artery samples were isolated from control, Type 2 diabetic Goto-Kakizaki (GK) rats and GK rats treated with ETA antagonist ABT-627. Gene expression profile of MMP-2, MMP-9, MT1-MMP, fibronectin, procollagen type 1, c-fos and c-jun, were determined by quantitative real-time (qRT) PCR. In addition, aortic gene expression profile was evaluated by an ECM & Adhesion Molecules pathway specific microarray approach.Analysis of the qRT-PCR data demonstrated a significant increase in mRNA levels of MMPs and ECM proteins as compared to control animals after 6 weeks of mild diabetes. Furthermore, these changes were comparable in aorta and mesentery samples. In contrast, treatment with ETA antagonist prevented diabetes-induced changes in expression of MMPs and procollagen type 1 in mesenteric arteries but not in aorta. Microarray analysis provided evidence that 27 extracellular matrix genes were differentially regulated in diabetes. Further qRT-PCR with selected 7 genes confirmed the microarray data.These results suggest that the expression of both matrix scaffold protein and matrix degrading MMP genes are altered in macro and microvascular beds in Type 2 diabetes. ETA antagonism restores the changes in gene expression in the mesenteric bed but not in aorta suggesting that ET-1 differentially regulates microvascular gene expression in Type 2 diabetes.

SUBMITTER: Song W

PROVIDER: S-EPMC1434726 | biostudies-literature | 2006 Feb

REPOSITORIES: biostudies-literature

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Type-2 diabetes-induced changes in vascular extracellular matrix gene expression: relation to vessel size.

Song WeiWei W Ergul Adviye A

Cardiovascular diabetology 20060217

<h4>Background</h4>Hyperglycemia-induced changes in vascular wall structure contribute to the pathogenesis of diabetic microvascular and macrovascular complications. Matrix metalloproteinases (MMP), a family of proteolytic enzymes that degrade extracellular matrix (ECM) proteins, are essential for vascular remodeling. We have shown that endothelin-1 (ET-1) mediates increased MMP activity and associated vascular remodeling in Type 2 diabetes. However, the effect of Type 2 diabetes and/or ET-1 on ...[more]

PMID: 16503991

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Project description:Myocardial extracellular matrix expansion and reduced coronary flow reserve (CFR) occur in patients with type 2 diabetes mellitus without heart failure or coronary artery disease. Because aldosterone is implicated in the pathophysiology of cardiac fibrosis and vascular injury, the aim of this study was to test the hypothesis that aldosterone is associated with extracellular matrix expansion and reduced CFR in type 2 diabetes mellitus. Patients with type 2 diabetes mellitus without evidence of coronary artery disease were recruited. Blood pressure, lipid management, and glycemic control were optimized over 3 months. Cardiac magnetic resonance imaging with T1 mapping was used to measure myocardial extracellular volume (ECV). Cardiac positron emission tomography was used to assess CFR. On a liberal, 250 mEq/day sodium diet, 24-hour urinary aldosterone and change in serum aldosterone with angiotensin II stimulation were measured. Fifty-three participants with type 2 diabetes (68% men, mean age 53 ± 7 years, mean body mass index 32.2 ± 4.3 kg/m², mean glycosylated hemoglobin 6.8 ± 0.7%, mean systolic blood pressure 126 ± 14 mm Hg) without infarction or ischemia by cardiac magnetic resonance and positron emission tomography were studied. Subjects had impaired CFR (2.51 ± 0.83) and elevated ECV (0.36 ± 0.05), despite normal echocardiographic diastolic function and normal left ventricular function. Myocardial ECV, but not CFR, was positively associated with 24-hour urinary aldosterone excretion (r = 0.37, p = 0.01) and angiotensin II-stimulated aldosterone increase (r = 0.35, p = 0.02). In a best-overall multivariate model (including age, gender, body mass index, glycosylated hemoglobin, and blood pressure), 24-hour urinary aldosterone was the strongest predictor of myocardial ECV (p = 0.004). In conclusion, in patients with type 2 diabetes mellitus without coronary artery disease, aldosterone is associated with myocardial extracellular matrix expansion. These results implicate aldosterone in early myocardial remodeling in type 2 diabetes mellitus.

Project description:Background and aimsAn association between hypoglycaemia and adverse cardiovascular events has been suggested from longitudinal and retrospective cohort studies. The complement pathway proteins in hypoglycemia are not well studied. Here, we hypothesized that these circulating proteins would be elevated in response to hypoglycemia in type 2 diabetes (T2D) through the inflammatory response.MethodsA prospective, parallel study in T2D (n = 23) and controls (n = 23). Subjects underwent insulin-induced hypoglycemia with blood sampling at baseline, hypoglycemia and post-hypoglycemia; SOMAscan proteomic analysis of complement pathway-related proteins, cytokines and inflammatory proteins was undertaken.ResultsAt baseline: Complement C2 (p < 0.05) and Factor B (p < 0.05) were elevated in T2D. At hypoglycemia: Complement C2 (p < 0.05) and Factor B (p < 0.01) remained elevated, whilst Factor I became elevated (p < 0.05) in T2D; Complement C4b became elevated in controls (p < 0.05). In the post-hypoglycemia follow up period, Complement C2, Factor B and Factor I remained elevated in T2D; in addition, Factor D, Factor H and mannose-binding protein C showed elevations in T2D, whilst properdin, complement C3b, Factor H-related protein 5, complement C1q and decay-accelerating factor (DAF) showed elevations in controls. Granger causality analysis showed that inflammatory proteins appeared to drive complement protein changes in T2D; conversely, in controls, complement proteins drove inflammatory protein changes.ConclusionsBaseline elevations in C2 and Factor B indicate upregulation of the complement pathway in T2D. Changes in complement pathway-related protein levels in response to hypoglycemia suggest both intrinsic and alternative pathway activation at 2-h that appears driven by the underlying inflammation in T2D and could contribute to a cardiovascular event.ClinicalTrials.gov NCT03102801. Date of registration April 6, 2017, retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT03102801?term=NCT03102801&draw=2&rank=1.

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Type-2 diabetes-induced changes in vascular extracellular matrix gene expression: relation to vessel size.

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Type-2 diabetes-induced changes in vascular extracellular matrix gene expression: relation to vessel size.

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