Abstract
BackgroundOxidative stress plays a key role in exacerbating diabetes and cardiovascular disease. Heme oxygenase-1 (HO-1), a stress response protein, is cytoprotective, but its role in post myocardial infarction (MI) and diabetes is not fully characterized. We aimed to investigate the protection and the mechanisms of HO-1 induction in cardiomyocytes subjected to hypoxia and in diabetic mice subjected to LAD ligation.MethodsIn vitro: cultured cardiomyocytes were treated with cobalt-protoporphyrin (CoPP) and tin protoporphyrin (SnPP) prior to hypoxic stress. In vivo: CoPP treated streptozotocin-induced diabetic mice were subjected to LAD ligation for 2/24 h. Cardiac function, histology, biochemical damage markers and signaling pathways were measured.ResultsHO-1 induction lowered release of lactate dehydrogenase (LDH) and creatine phospho kinase (CK), decreased propidium iodide staining, improved cell morphology and preserved mitochondrial membrane potential in cardiomyocytes. In diabetic mice, Fractional Shortening (FS) was lower than non-diabetic mice (35±1%vs.41±2, respectively p<0.05). CoPP-treated diabetic animals improved cardiac function (43±2% p<0.01), reduced CK, Troponin T levels and infarct size compared to non-treated diabetic mice (P<0.01, P<0.001, P<0.01 respectively). CoPP-enhanced HO-1 protein levels and reduced oxidative stress in diabetic animals, as indicated by the decrease in superoxide levels in cardiac tissues and plasma TNFα levels (p<0.05). The increased levels of HO-1 by CoPP treatment after LAD ligation led to a shift of the Bcl-2/bax ratio towards the antiapoptotic process (p<0.05). CoPP significantly increased the expression levels of pAKT and pGSK3β (p<0.05) in cardiomyocytes and in diabetic mice with MI. SnPP abolished CoPP's cardioprotective effects.ConclusionsHO-1 induction plays a role in cardioprotection against hypoxic damage in cardiomyocytes and in reducing post ischemic cardiac damage in the diabetic heart as proved by the increased levels of pAKT with a concomitant inhibition of pGSK3β leading to preserved mitochondrial membrane potential.
Highlights
Ischemia-induced cell necrosis and apoptosis are major contributors to cardiac dysfunction in ischemic heart disease It is recognized that mitochondrial dysfunction plays a crucial role in the pathogenesis of cell death induced by myocardial ischemia [1]
CoPP suppressed the release of lactate dehydrogenase (LDH) in cardiomyocytes that had undergone exposure to hypoxia
The release of LDH and creatine phospho kinase (CK) after 2 h of hypoxia was lower in the group treated with CoPP compared with the untreated group
Summary
Ischemia-induced cell necrosis and apoptosis are major contributors to cardiac dysfunction in ischemic heart disease It is recognized that mitochondrial dysfunction plays a crucial role in the pathogenesis of cell death induced by myocardial ischemia [1]. The key factor responsible for mPTP opening is mitochondrial calcium overload, especially when this is accompanied by oxidative stress, adenine nucleotide depletion, elevated phosphate concentrations, and mitochondrial depolarization [4,5,6]. HO-1 plays an important role in cellular protection against oxidative insult in cardiovascular disease, including diabetes, and in the alleviation of vascular diseases. Heme degradation generates biliverdin and bilirubin, which possess potent antioxidant properties [8] and are cytoprotective in the cardiovascular system [9]. HO-1 plays an important role in maintaining redox status within the heart, thereby protecting against oxidative insult. Oxidative stress plays a key role in exacerbating diabetes and cardiovascular disease. Heme oxygenase-1 (HO1), a stress response protein, is cytoprotective, but its role in post myocardial infarction (MI) and diabetes is not fully characterized. We aimed to investigate the protection and the mechanisms of HO-1 induction in cardiomyocytes subjected to hypoxia and in diabetic mice subjected to LAD ligation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
