N-Acetylcysteine and Allopurinol Confer Synergy in Attenuating Myocardial Ischemia Injury via Restoring HIF-1α/HO-1 Signaling in Diabetic Rats

Abstract

ObjectivesTo determine whether or not the antioxidants N-acetylcysteine (NAC) and allopurinol (ALP) confer synergistic cardioprotection against myocardial ischemia/reperfusion (MI/R) injury by stabilizing hypoxia inducible factor 1α (HIF-1α)/heme oxygenase 1 (HO-1) signaling in diabetic myocardium.MethodsControl or diabetic [streptozotocin (STZ)-induced] Sprague Dawley rats received vehicle or NAC, ALP or their combination for four weeks starting one week after STZ injection. The animals were then subjected to thirty minutes of coronary artery occlusion followed by two hours reperfusion in the absence or presence of the selective HO-1 inhibitor, tin protoporphyrin-IX (SnPP-IX) or the HIF-1α inhibitor 2-Methoxyestradiol (2ME2). Cardiomyocytes exposed to high glucose were subjected to hypoxia/re-oxygenation in the presence or absence of HIF-1α and HO-1 achieved by gene knock-down with related siRNAs.ResultsMyocardial and plasma levels of 15-F2t-isoprostane, an index of oxidative stress, were significantly increased in diabetic rats while cardiac HO-1 protein and activity were reduced; this was accompanied with reduced cardiac protein levels of HIF-1α, and increased post-ischemic myocardial infarct size and cellular injury. NAC and ALP given alone and in particular their combination normalized cardiac levels of HO-1 and HIF-1α protein expression and prevented the increase in 15-F2t-isoprostane, resulting in significantly attenuated post-ischemic myocardial infarction. NAC and ALP also attenuated high glucose-induced post-hypoxic cardiomyocyte death in vitro. However, all the above protective effects of NAC and ALP were cancelled either by inhibition of HO-1 or HIF-1α with SnPP-IX and 2ME2 in vivo or by HO-1 or HIF-1α gene knock-down in vitro.ConclusionNAC and ALP confer synergistic cardioprotection in diabetes via restoration of cardiac HIF-1α and HO-1 signaling.

Repeated Non-Invasive Limb Ischemic Preconditioning Confers Cardioprotection Through PKC-Ԑ/STAT3 Signaling in Diabetic Rats

“…Twenty-four hours after the completion of rNLIP, the rats were subjected to myocardial I/ RI. Rats in the respective subgroups were anesthetized using phenobarbital sodium; ischemia was achieved by occluding the left anterior descending (LAD) artery for 30 minutes followed by reperfusion for 2 hours as described [28]. Infarct size (IS) was assessed using TTC (1% 2, 3, 5-triphenyltetrazolium chloride) staining and expressed as a percentage of the anatomic area at risk (AAR) [29, 30].…”

Allopurinol reduces oxidative stress and activates Nrf2/p62 to attenuate diabetic cardiomyopathy in rats

“…22 The daily dose of ALP (100 mg/kg) was dissolved into 2/3 volume of the average daily amount of drinking water that was estimated based on preliminary study and previous studies to ensure that the total amount of ALP was taken by the rats before additional amount of water was supplied. ALP (Sigma-Aldrich) were dissolved in drinking water for 4 weeks' duration of treatment starting 1 week after induction of diabetes.…”

“…18 It attenuates the diabetes-induced increase of myocardial xanthine oxidase activity, 19,20 reduces ROS production and improves diabetes-induced cardiac dysfunction. 22 We suggested that the hyperglycaemia-induced oxidative stress and the over-activation of myocardial autophagy are key mechanisms that cause the imbalance of Nrf2-Keap1-p62 and the development of DCM. 22 We suggested that the hyperglycaemia-induced oxidative stress and the over-activation of myocardial autophagy are key mechanisms that cause the imbalance of Nrf2-Keap1-p62 and the development of DCM.…”

Associations of proteins relevant to MAPK signaling pathway (p38MAPK-1,HIF-1 and HO-1) with coronary lesion characteristics and prognosis of peri-menopausal women

“…Notably, HIF-1 was subject to regulation of estrogen via correlated Akt and p38-mitogen activated protein kinase (p38MAPK) pathways, implying that HIF-1 might emerge as the featured biomarker between premenopausal and postmenopausal populations [11]. In addition, since HIF-1/HO-1 signaling pathway was involved with the molecular mechanism that contributed to development of myocardial ischemia, HO-1 was also incorporated as a candidate protein that could be modified by estrogen [12, 13]. Besides, p38MAPK appeared to be commonly investigated in the area of myocardial inflammation, rather than CAD, yet it functioned as the upstream molecule of HIF-1 [14].…”