We and others have previously demonstrated that heme oxygenase-1 (HO-1) induction by acute hemin administration exerted cardioprotective effects. Here we developed a rat model of heart failure to investigate whether a long-term induction of HO-1 by chronic hemin administration exerted protective effects. Sprague Dawley rats, undergoing permanent ligation of the left coronary artery, were closely monitored for survival rate analysis and sacrificed on day 28 postoperation. Administration of hemin (4 mg/kg) every other day for 4 weeks induced a massive increase in HO-1 expression and activity, as shown by the increased levels of the two main metabolic products of heme degradation, bilirubin and carbon monoxide (CO). These effects were associated with significant improvement in survival and reduced the extension of myocardial damage. The ischemic hearts of the hemin-treated animals displayed reduced oxidative stress and apoptosis in comparison with the non-treated rats as shown by the decreased levels of lipid peroxidation, free radical-induced DNA damage, caspase 3 activity and Bax expression. Besides, chronic HO-1 activation suppressed the elevated levels of MPO activity, IL-1β and TNF-α production evoked by the ischemic injury and increased the plasma level of the anti-inflammatory cytokine IL-10. Interestingly, HO-1 inhibitor zinc protoporphyrin IX (ZnPP-IX, 1 mg/kg) lowered bilirubin and CO concentrations to control values, thus abolishing all the cardioprotective effects of hemin. In conclusion, the results demonstrate that chronic HO-1 activation by prolonged administration of hemin improves survival and exerts protective effects in a rat model of myocardial ischemia by exerting a potent antioxidant activity and disrupting multiple levels of the apoptotic and inflammatory cascade.
- Received December 11, 2012.
- Accepted April 15, 2013.
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