Impairment of Heme Oxygenase Expression in Immuno-suppressed Mice Exacerbates Ischemic Heart Myocyte Cell Death: Reversible by Bilirubin and Restoration of Nitric Oxide

Abstract

Background: Cardiovascular risk and therapy inimmuno-deficient patients is a challenge for cardiologists. Nitric oxide (NO) plays a central role in vascular response to ischemicdamage by decreasing microvascular resistance and is an important regulator of the immune system. The aim of this study was to assess theefficacy of restoration of HO-1 and whether the increase in bilirubin levelsattenuates cardiac remodeling in immuno-suppressed mice. Method: Myocardial infarction was inducedby LAD ligation in immunosuppressive (BALB SCID) mice. Mice comprised 4 groups: sham, MI, MItreated with the HO-1 inducer CoPP with and without HO activity inhibitor, SnMP.Results: Mice with MI had increasedlevels of inflammatory cytokines, myocardial fibrosis and myocyte death (p<0.05)as compared to control animals. Left ventricle end diastolic area (EDA) wasreduced and fractional area change (FAC) and angiogenesis was increased(p<0.01) in CoPP-treated mice compared to the MI group. Inflammation,cardiac iNOS expression, myocardial cell death and fibrosis were reduced inCoPP treated animals as a result of increased bilirubin levels (p<0.05)serum nitrite levels were increased. Foxp3 (marker of T regulatory cells), pAMPK, pAKT expression in cardiac tissues wasincreased in CoPP-treated animals. SnMP reversed these positive cardiaceffects. Conclusion: This novelstudy suggests a critical role of HO-1 –mediated increase in bilirubin inimproving cardiac function and microvascular tone control after onset of MI inimmuno-suppressed mice through the modulation of nitric oxide synthaseexpression.