Heme Oxygenase-1 Induction Improves Cardiac Function following Myocardial Ischemia by Reducing Oxidative Stress

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.

Cardiomyocyte-specific Bmal1 deletion in mice triggers diastolic dysfunction, extracellular matrix response, and impaired resolution of inflammation

“…Significant increase in the proinflammatory transcripts viz ccl2, Il-1␤, ccl8, and ccr2 (neutrophil chemotaxis and leukocyte migration genes), with no change in the proresolving/alternative transcript Il-10 and Il-13, in CBK mice indicates an impaired defensive mechanism to repair inflammation at 28 wk of age. This was further supported by decreased levels of 5-LOX, COX-2, and HO-1 (3,17,19), impairing the resolution of the inflammation axis. Thus an age-related defective resolution of inflammation and dilative ventricular dysfunction leads to reduced survival (42) with marked cardiomyopathy.…”

“…Thus, to understand how Bmal1 deletion affects the inflammation-resolution axis at 28 wk, we determined mRNA levels of resolving genes. The CBK mice showed a significant decrease in proresolving transcripts of Hmox-1, Alox5, and Ptgs-2 (3,17,19) with no change in levels of inflammation promoting transcripts Alox12 and Alox15 (21) compared with age-matched controls (Fig. 6, A and B).…”

Combined iron sucrose and protoporphyrin treatment protects against ischemic and toxin-mediated acute renal failure

“…First, we observed a 2-3 fold increase in HO-1 enzymatic activity at 18 hrs post FeS/SnPP treatment, confirming active HO-1 generation (i.e., vs. production of a ‘dead’ enzyme). Second, we utilized a functional way (29) of determining HO-1's enzymatic participation in the observed cytoresistance. To this end, we preconditioned mice with FeS/SnPP, driving up renal HO-1 protein levels, and then 18 hrs later, we administered SnPP to inhibit the pre-formed HO-1 activity at the time of injury induction.…”

Tumor necrosis factor alpha protects heart cultures against hypoxic damage via activation of PKA and phospholamban to prevent calcium overload

“…We have recently demonstrated that when cultured cardiomyocytes were treated with cobalt protoporphyrin (CoPP), prior to hypoxic stress, HO-1 levels were increased and the hypoxic damage was reduced. Tin protoporphyrin (SnPP) abolished the beneficial effects of CoPP pretreatment (Issan et al 2014). It is unlikely that TNF␣ protected the cardiac cells from hypoxia by inducing HO-1, as it has been demonstrated that HO-1 induction reduces the levels of inflammatory cytokines such as TNF␣, IL-6, and IL-1␤; a process that is reversed by inhibiting HO activity (Hosick and Stec 2012).…”