Beneficial effect of prolonged heme oxygenase 1 activation in a rat model of chronic heart failure

• Published in: Disease models & mechanisms 2013-07, Vol.6 (4), p.1012-1020
• Main Authors: Collino, Massimo, Pini, Alessandro, Mugelli, Niccolò, Mastroianni, Rosanna, Bani, Daniele, Fantozzi, Roberto, Papucci, Laura, Fazi, Marilena, Masini, Emanuela
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Biomarkers - metabolism; Blood vessels; Carbon Monoxide - metabolism; Cardiomyocytes; Cardiovascular disease; Coronary vessels; Disease Models, Animal; DNA Damage; Edema; Enzyme Activation - drug effects; Free Radicals - metabolism; Heart attacks; Heart failure; Heart Failure - enzymology; Heart Failure - pathology; Heart Failure - physiopathology; Heart Function Tests - drug effects; Heart Ventricles - drug effects; Heart Ventricles - pathology; Heart Ventricles - physiopathology; Heart Ventricles - ultrastructure; Heme Oxygenase-1 - metabolism; Hemin - pharmacology; Ischemia; Leukocytes - drug effects; Leukocytes - metabolism; Lipid Peroxidation - drug effects; Male; Myocardial Infarction - diagnostic imaging; Myocardial Infarction - enzymology; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardial Reperfusion Injury - diagnostic imaging; Myocardial Reperfusion Injury - enzymology; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - physiopathology; Oxidative stress; Oxidative Stress - drug effects; Physiology; Rats; Rats, Sprague-Dawley; Rodents; Signal Transduction - drug effects; Survival Analysis; Ultrasonography; Vein & artery diseases; Ventricular Function, Left - drug effects
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.011528

We and others have previously demonstrated that heme oxygenase 1 (HO-1) induction by acute hemin administration exerts 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 that underwent permanent ligation of the left coronary artery were closely monitored for survival rate analysis and sacrificed on day 28 post-operation. Administration of hemin (4 mg/kg body weight) 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 myeloperoxidase (MPO) activity, interleukin 1β (IL-1β) production and tumor necrosis factor-α (TNFα) production that were 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.