High Dose Ramipril Inhibits Connective Tissue Growth Factor Expression and Fibrosis in Type 2 Diabetic Rat Heart.
10.4070/kcj.2006.36.9.635
- Author:
Kyoung Ho CHOI
1
;
Sang Hong BAEK
;
Won Jae LEE
;
Kye Nam PARK
;
Pum Joon KIM
;
Ki Bae SEUNG
;
Jang Seong CHAE
;
Jae Hyung KIM
;
Kyu Bo CHOI
Author Information
1. Department of Emergency Medicine, The Catholic University of Korea, College of Medicine, Seoul, Korea.
- Publication Type:Original Article
- Keywords:
Receptor of advanced glycation end products;
Connective tissue growth factor;
Fibrosis;
Ramipril
- MeSH:
Angiotensin-Converting Enzyme Inhibitors;
Animals;
Collagen;
Coloring Agents;
Connective Tissue Growth Factor*;
Connective Tissue*;
Diabetic Cardiomyopathies;
Fibrosis*;
Glycosylation End Products, Advanced;
Heart*;
Hydroxyproline;
Oxidative Stress;
Rage;
Ramipril*;
Rats*;
Rats, Inbred OLETF
- From:Korean Circulation Journal
2006;36(9):635-643
- CountryRepublic of Korea
- Language:Korean
-
Abstract:
BACKGROUND AND OBJECTIVES: Connective tissue growth factor (CTGF) is a profibrotic cytokine, which may play an important role in the development of diabetic cardiovascular complications. ACE inhibition significantly prevents cardiovascular events in diabetics, although the mechanism remains obscure. The purpose of this study was to explore the effect of ACE inhibitors on the expression of CTGF and oxidative stress in the diabetic heart, and determine the effects of long term treatment with ACE inhibitors on diabetic cardiomyopathy. MATERIALS AND METHODS: Thirty OLETF (Otsuka Long Evans Tokushima Fatty) diabetic and thirty LETO (Long Evans Tokushima Otsuka) nondiabetic control rats were randomized into four groups for 24 weeks of treatment with either ramipril (5 mg/kg/day, n=15, each groups) or saline (n=15, each groups). RESULTS: The OLETF diabetic rats had prominent perivascular fibrosis, as shown by picrosirius red stains, compared to the LETO nondiabetic rats. ACE inhibition significantly prevented perivascular fibrosis in OLETF rats (p<0.01). Immunohistochemical stains were used to detect proteins for the receptors of advanced glycation end products (RAGE), CTGF, collagen III and nitrotyrosine. Although there were no significant differences in the myocardiac collagen contents, as found by measuring the hydroxyproline concentration among the four groups, the OLFTF diabetic rats had significantly increased cardiac CTGF and collagen III protein expression compared with the nondiabetic rats. The ACE inhibitor attenuated the increases in RAGE (-50.3%; p<0.01), CTGF (-37.5%; p<0.01) and collagen III (-52.3%; p<0.01) expression in the diabetic heart microvascular area. The OLFTF rats showed marked an increment in cardiac nitrotyrosine, a marker of protein oxidation. Ramipril also inhibited the expression of cardiac nitrotyrosine (-78.3%; p<0.01). CONCLUSION: The present study shows a possible role of RAGE/nitrotyrosine/CTGF in the diabetic cardiomyopathy of OLETF rats. The long term treatment of high dose ACE inhibitors may have beneficial effects on the diabetic heart through both antioxidant and antifibrotic mechanisms.
