Advanced Glycation End Product-Mediated Matrix Metallo-proteinase-9 and Apoptosis via Renin-Angiotensin System in Type 2 Diabetes

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Abstract
Aim: Advanced glycation end products (AGE) play a key role in diabetic vascular complications, whereas matrix metalloproteinases (MMPs) and apoptosis contribute to plaque instability. This study was conducted to investigate the association of AGE-mediated MMP-9 and apoptosis with the renin?angiotensin system (RAS). We also examined the correlation between plasma HbA1c levels and plaque parameters. Methods: We used autopsy specimens from the aortae and coronary arteries of patients with or without diabetes (n=11, each group) for the immunohistochemistry of AGE, MMP-9, angiotensin-converting enzyme (ACE), and the receptor for AGE (RAGE). Apoptosis was determined by TUNEL staining. Results: The proportions of AGE accumulation, MMP-9 expression and apoptosis in intimal areas of both aortic and coronary specimens of diabetics were greater than in nondiabetics. MMP-9 expression and apoptosis were correlated with AGE accumulation. RAGE expression was significantly increased in diabetic specimens compared to nondiabetes. Interestingly, the expression of ACE in diabetic specimens was increased and also correlated with AGE accumulation, RAGE expression, MMP-9 expression, and apoptosis in all specimens from diabetics and nondiabetics. Plasma levels of HbA1c were linearly correlated with AGE accumulation, MMP-9, apoptosis, and ACE expression. Conclusion: The present study shows that AGE/RAGE-related MMP-9 expression and apoptosis were correlated with ACE expression in diabetic plaques and that RAS may be involved in AGE-dependent diabetic vascular complications.

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