Heme Oxygenase-1 Induction Improves Cardiac Function following Myocardial Ischemia by Reducing Oxidative StressReportar como inadecuado




Heme Oxygenase-1 Induction Improves Cardiac Function following Myocardial Ischemia by Reducing Oxidative Stress - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Background

Oxidative 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.

Methods

In 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.

Results

HO-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.

Conclusions

HO-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.



Autor: Yossi Issan, Ran Kornowski, Dan Aravot, Asher Shainberg, Michal Laniado-Schwartzman, Komal Sodhi, Nader G. Abraham, Edith Hochhau

Fuente: http://plos.srce.hr/



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