Heme oxygenase improves cardiac function by decreasing oxidative stress

HO-1 plays an important role in maintaining redox status within the heart, thereby protecting against oxidative insult. HO-1 gene expression reverses ischemic heart injury and prevents vascular dysfunction in experimental diabetes. CoPP, an inducer of HO-1, protects human cardiac stem cells against apoptosis through the activation of the ERK/Nrf2 signaling pathway. CoPP treatment in hypoxic cells reduced cell damage as measured by lower levels of LDH and CK, maintained cell morphology and increased the viability of cardiomyocytes following hypoxia, as seen by propidium iodide (PI) staining. CoPP also preserved mitochondrial membrane potential.

Mitochondrial membrane potential depolarization is an early event in the intrinsic apoptotic pathway activated by hypoxia. Inhibition of HO activity by SnPP abolished the beneficial effect of CoPP-pretreatment in the cardiomyocyte culture subjected to hypoxia. Also CoPP improved cardiac function as seen by increased FS, reduced infarct size and biochemical markers of myocardial injury in diabetic mice after LAD ligation. HO-1 is a rapidly inducible cytoprotective protein that degrades heme to biliverdin, ferrous iron, and carbon monoxide (CO). HO-1 plays an important role in maintaining redox status within the heart, and protects the vital organ against oxidative insult. In our diabetic mice, we observed that CoPP treatment decreased oxidative stress as seen by lower levels of superoxide. HO-1 also increased the levels of adiponectin. The increase in adiponectin was associated with a significant decrease in TNF-a. The dysfunction of adipose tissue, characterized by the infiltration of inflammatory cells and the aberrant production of adipokines, is a key link between obesity and cardiovascular disease. It was addressed with HO-1 expression in the porcine heart, suggesting a potential role of HO-1 in the defense against pathophysiological stress. The HO-1-mediated protection from myocardial ischemia/reperfusion injury was associated with a decrease in oxidative stress and pro-apoptotic and pro-inflammatory protein levels. In experimental diabetes models, overexpression of HO-1 prevented vascular dysfunction and attenuated oxidative stress-dependent endothelial cell damage. HO-1 overexpression promoted neovascularization and ameliorated apoptosis in a heart failure model.

The cytoprotective properties of HO-1 have been attributed to the degradation of heme and the beneficial effects of its by-products, bilirubin and carbon monoxide (CO). Cells overexpressing HO-1 exhibit low levels of free iron because of the upregulation of ferritin and the extraction of iron into the extracellular space. The byproducts of heme degradation (bilirubin, CO, and iron as ferritin) exert actions that protect the cell from oxidative damage and death. HO-1 may also exert cytoprotective effects, independent of heme breakdown by interacting with survival signaling pathways. HO-1 elevated adiponectin levels are associated with increased heart eNOS and pAKT levels, both of which increase resistance to oxidants and cell survival. It was also demonstrated that the protective effect that results from the induction of HO-1 is via activation of the AKT pathway, inhibition of GSK3b and protection of the mitochondria and its function in cardiomyocytes subjected to hypoxia. We hereby illustrate that in cardiomyocyte cultures CoPP preserves the mitochondrial membrane potential. Ischemic preconditioning preserves mitochondrial membrane potential and limits reactive oxygen species production in rat hearts.