Abstract 4043: Blockade of Renin-Angiotensin System (RAS) Inhibits Increased Matrix Metalloproteinase-9 Expression and Apoptosis Induced by Advanced Glycation End Products (AGE) and Attenuates Receptor for AGE (RAGE) Expression
Background: Diabetes is a major risk factor of coronary artery disease (CAD). AGE accumulate and RAGE expression increases in the vascular wall of type 2 diabetes, which promotes vascular remodeling in the diabetes. However, the role of an AGE/RAGE system in the pathogenesis of CAD is not fully understood. Matrix metalloproteinases (MMPs) and apoptosis play crucial roles in plaque instability. Our previous study showed that the plasma HbA1c levels were correlated with AGE accumulation, MMP-9 expression and apoptosis in plaques. Recent clinical trials have shown that blockade of RAS suppresses the onset of the diabetes.
Hypothesis: We hypothesize that an AGERAGE axis plays an essential role in diabetic vascular remodeling including plaque instability and RAS is profoundly associated with the AGERAGE axis.
Methods: We used the autopsy specimens of aortic and coronary atherosclerotic lesions in patients with or without type 2 diabetes mellitus (n=11, each group) for immunohistochemistry of AGE, RAGE, MMP-9 and angiotensin converting enzyme (ACE). Apoptosis was determined by a TUNEL method. In a human smooth muscle cell (SMC) culture system, we examined the effects of an ACE inhibitor (temocaprilat, Sankyo) and an angiotensin II type 1 receptor antagonist (olmesartan, Sankyo) on AGE-triggered MMP-9 expression and apoptosis, whereas ACE mRNA levels were measured by RT-PCR.
Results: The proportions of AGE, RAGE, MMP-9 and ACE of both aortic and coronary specimens in the diabetes were significantly greater than those in the non-diabetes, whereas the diabetic specimens had increased percentages of apoptosis compared with those of non-diabetes (P<0.01). In plaques, ACE expression was significantly correlated with AGE accumulation, MMP-9 expression and apoptosis. In cultured SMCs, AGE directly up-regulated ACE mRNA, and increased MMP-9 and RAGE expression as well as apoptosis. Interestingly, blockade of RAS by both temocaprilat and olmesartan attenuated AGE-triggered MMP-9 expression and apoptosis as well as the RAGE expression.
Conclusions: The present study provides evidence that RAS plays a central role in AGE/RAGE-dependent vascular remodeling in diabetes, suggesting that blockade of RAS is a good strategy to treat CAD complicated with diabetes.