Korean Circ J.  2006 Sep;36(9):635-643. 10.4070/kcj.2006.36.9.635.

High Dose Ramipril Inhibits Connective Tissue Growth Factor Expression and Fibrosis in Type 2 Diabetic Rat Heart

• Choi KH
• Baek SH
• Lee WJ
• Park KN
• Kim PJ
• Seung KB
• Chae JS
• Kim JH
• Choi KB

• KMID: 1895027
• DOI: http://doi.org/10.4070/kcj.2006.36.9.635

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.

Keyword

Receptor of advanced glycation end products; Connective tissue growth factor; Fibrosis; Ramipril

MeSH Terms

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
Angiotensin-Converting Enzyme Inhibitors
Collagen
Coloring Agents
Connective Tissue Growth Factor
Glycosylation End Products, Advanced
Hydroxyproline
Ramipril