© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
VEGF-mediated angiogenesis is impaired by angiotensin type 1 receptor blockade in cardiomyopathic hamster hearts
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan
* Corresponding author. Tel.: +81-11-716-1161; fax: +81-11-706-7874. okamotoh{at}hucc.hokudai.ac.jp
Objective: Coronary microcirculation plays an important role in the progression of cardiac remodeling. Among angiogenic factors, it has been reported that angiotensin II may contribute to neovascularization. However, it is unknown whether inhibition of the renin–angiotensin system suppresses angiogenesis, especially within the heart. Our aim was to evaluate the effects of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin II receptor type I blocker valsartan on cardiac microvasculature, function, vascular endothelial growth factor (VEGF) expression, and survival in cardiomyopathic hamsters. Methods: Male cardiomyopathic hamsters (BIO TO2) were administered either a placebo (group C), enalapril (30 mg/kg/day) (group E), or valsartan (40 mg/kg/day) (group V), starting at the age of 6 weeks. This continued until death. Hemodynamic study, histological analysis, and northern blot analysis were performed at 39 weeks. Results: Group V showed significant increases in percent fibrosis, end diastolic pressure, and LV dP/dt min, and significant decreases in percent fractional shortening, LV dP/dt max, capillary density, and the level of mRNA expression of VEGF compared with group C. Group E showed significant increases in percent fractional shortening while the capillary density and level of mRNA expression of VEGF were unchanged. The 300-day survival rate was significantly lower in group V (25.0%) but higher in group E (100%) than that of group C (66.7%). Conclusions: Therapy with valsartan may have adverse effects on survival rate concomitant with the progression of cardiac remodeling owing to impaired VEGF-mediated angiogenesis. Therapy with enalapril has a neutral effect on VEGF-mediated angiogenesis, leading to the suppression of cardiac remodeling and an increase in life expectancy.
KEYWORDS %FS, percent fractional shortening; ACEI, angiotensin-converting enzyme inhibitor; AII, angiotensin II; ARB, angiotensin type I receptor blockade; AST, asparaginate amino transferase; ATI receptor, angiotensin type I receptor; BK, bradykinin; BW, body weight; Cr, creatinine; DAB, 3',3'-diaminobenzidine; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GSA-B4, the lectin Griffonia simplicifolia; HR, heart rate; LV, left ventricular; LV dP/dt max, the maximum rate of rise in left ventricular pressure; LV dP/dt min, the maximum rate of fall in left ventricular pressure; LVDd, left ventricular end-diastolic dimension; LVEDP, left ventricular end-diastolic pressure; LVSP, left ventricular systolic pressure; LVW, left ventricular weight; NO, nitric oxide; PBS, phosphate-buffered saline; PG, prostaglandins; RAS, the renin–angiotensin system; SR, synchrotron radiation; VEGF, vascular endothelial growth factor
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