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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Song
WeiWei
W
Program in Clinical and Experimental Therapeutics, The University of Georgia College of Pharmacy, Augusta, Georgia 30912, USA. wsong@temple.edu
Ergul
Adviye
A
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D000077868:Atrasentan; D001808:Blood Vessels / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006943:Hyperglycemia / Q000150:complications; D008297:Male; D020782:Matrix Metalloproteinases / Q000187:drug effects / Q000235:genetics*; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D020782:Matrix Metalloproteinases; D000077868:Atrasentan