Abstract 11423: A Direct Renin Inhibitor Negates Ischemia-Induced Cardiac Remodeling with Chronic Kidney Disease through Oxidative Stress Reduction in Mice
Background: The complex pathophysiological interactions between heart and kidney diseases are known as the cardiorenal syndrome. The renin-angiotensin system (RAS) may play a pivotal role in the development of cardiorenal syndrome. However, detailed mechanisms are to be elucidated.
Hypothesis: We assessed the hypothesis that RAS plays a pivotal role in the development of contraction failure and pathological remodeling after myocardial infarction (MI) with renal failure.
Methods: To establish the type IV cardiorenal syndrome model, five/six nephrectomy (NTX) was performed followed by the induction of MI by a coronary artery ligation 28 days later in mice. The animals were administered daily with a subcutaneous injection of direct renin inhibitor (DRI) (aliskiren, 25mg/kg/day) or vehicle after NTX. The hearts were harvested on day 28 after MI and were used for pathological and molecular analysis.
Results: MI plus NTX resulted in impaired LV ejection fraction (EF) (36.4 ± 2.2%; n = 8) compared to MI alone (53.8 ± 2.6%; n = 10), however, DRI significantly improved the value (EF: 65.4 ± 2.4%; n = 11; P < 0.05). Pathologically, collagen distribution in the MI plus NTX hearts expanded (19.3 ± 2.4%; n = 8), however, DRI treatment significantly suppressed the area (6.8 ± 2.0%; n = 11; P < 0.05). These pathophysiological changes were independent of renal function and blood pressure. Moreover, MI plus NTX hearts showed further elevation of Nox2, Nox4, and MCP-1 mRNA levels compared to the MI hearts without NTX. DRI treatment suppressed these changes in the MI-induced NTX mice. In vitro study revealed that Nox2 expression was elevated in isolated neonatal cardiomyocytes by the stimulation of plasma from NTX mice. However, Nox2 up-regulation was negated when plasma from DRI-treated-NTX mice was administered.
Conclusions: Our data suggest that renal disorder results in ventricular dysfunction and deteriorates myocardial remodeling after MI through excessive RAS activation and oxidative stress. Thus, direct renin inhibition may significantly prevent LV remodeling after MI with renal failure.
- © 2011 by American Heart Association, Inc.