Advanced glycation end product-mediated matrix metallo-proteinase-9 and apoptosis via renin-angiotensin system in type 2 diabetes.
OBJECTIVE
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.


CONCLUSIONS
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.
Ishibashi
Toshiyuki
T
Department of Cardiology and Hematology, Fukushima Medical University, Fukushima 960-1295, Japan.
Kawaguchi
Michiko
M
Sugimoto
Koichi
K
Uekita
Hironori
H
Sakamoto
Nobuo
N
Yokoyama
Keiko
K
Maruyama
Yukio
Y
Takeishi
Yasuchika
Y
D001011:Aorta / Q000473:pathology; D017209:Apoptosis; D016022:Case-Control Studies; D003331:Coronary Vessels / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology*; D003925:Diabetic Angiopathies / Q000209:etiology; D017127:Glycation End Products, Advanced / Q000032:analysis; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000032:analysis*; D007703:Peptidyl-Dipeptidase A / Q000032:analysis*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000032:analysis*; D012084:Renin-Angiotensin System; D018631:ras Proteins
D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D007703:Peptidyl-Dipeptidase A; D020780:Matrix Metalloproteinase 9; D018631:ras Proteins