| Summary: | <p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>Aorta and mesenteric artery samples were isolated from control, Type 2 diabetic Goto-Kakizaki (GK) rats and GK rats treated with ET<sub>A </sub>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.</p> <p>Results</p> <p>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. Futhermore, these changes were comparable in aorta and mesentery samples. In contrast, treatment with ET<sub>A </sub>antagonist prevented diabetes-induced changes in expression of MMPs and procollagen type 1 in mesenteric arteries but not in aorta. Microaarray analysis provided evidence that 27 extracellular matrix genes were differentially regulated in diabetes. Further qRT-PCR with selected 7 genes confirmed the microarray data.</p> <p>Conclusion</p> <p>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. ET<sub>A </sub>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.</p>
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