Heme Oxygenase System in Myocardial Infarction and Cardio-renal syndrome

Myocardial infarction (MI) is a major cause of morbidity and mortality in the developing as well as developed world. Heart undergoes severe left ventricular remodeling, after MI which may eventually progress to heart failure. Newer strategies are required to protect the infarcted myocardium against ischemic injury and enhance repair of the infarcted heart. Cardio-renal syndrome (CRS) is another clinical problem which arises from the decompensated heart failure post-MI. CRS is characterized by acute kidney dysfunction and renal vasoconstriction and is mediated by renin angiotensin aldosterone (RAAS) axis and sympathetic nervous system (SNS) leading to renal failure. Recent findings implicate immune system in playing an important role in the development of CRS. The present studies were undertaken to investigate the role of Heme oxygenase-1 (HO-1) in protection and repair of infarcted heart and to examine the potential mechanisms mediating the protective effects of HO-1 in experimental mouse models. In addition, we also investigated the role of HO-1 as well as immune system in the development of CRS by using Lymphocyte suppressed SCID mice.;A total of 250 adult mice were used in the experimental studies (125 C57 mice and 125 SCID mice). An experimental MI model was induced by left anterior descending (LAD) artery ligation and effects of HO-1 induction on ventricular remodeling as well as on cardiorenal syndrome was examined. Echocardiography was used to assess the ventricular function and renal Doppler was used to record the renovascular resistance. Histological and Immunohistochemical techniques were used to assess cardiac angiogenesis, cardiac fibrosis, cardiac necrosis and renal fibrosis.;In the experimental studies, HO-1 expression was induced pharmacologically by Cobalt Protoporphyrin (CoPPIX) and Stannous Mesoporphyrin (SnMP) was used to inhibit the activity of HO and served as negative control. HO-1 induction promoted angiogenesis in infarcted hearts via vascular endothelial growth factor (VEGF) and Ets-1. In addition, HO-1 showed many beneficial effects on cellular and extracellular remodeling in the infarcted heart. We noticed improved cardiac energy metabolism with the treatment of CoPP. HO-1 favored fatty acid oxidation to meet the high energy demand of an infarcted heart.;We also investigated the role of HO-1 in CRS-1 in conjunction with immune system by using immunosuppressive and immunocompetent mice. We found that HO-1 has the potential to ameliorate CRS-1 in both SCID and C57 mice. Our study demonstrated that HO-1 dependent improvement in CRS-1 is more evident in immunosuppressed mice than in immunocompetent mice. This novel study indicates the modulatory role of immune cells in HO-1 dependent improvement of CRS-1 in experimental MI mouse model.;In conclusion, HO-1 in the experimental murine MI models played an important role in the recovery and repair of infarcted hearts by increasing angiogenesis, improving cardiac energy metabolism and decreasing myocardial fibrosis. Induction of HO-1 also ameliorated CRS in post MI mouse model.