Heme Oxygenase-1 and the Ischemia-Reperfusion Injury in the Rat Heart

Abstract

Carbon monoxide (CO) is a signaling gas produced intracellularly by heme oxygenase (HO) enzymes using heme as a substrate. During heme breakdown, HO-1 and HO-2 release CO, biliverdin, and Fe(2+). In this study, we investigated the effects of manipulation of the HO-1 system in an in vivo model of focal ischemia-reperfusion (FIR) in the rat heart. Male Wistar albino rats, under general anesthesia and artificial ventilation, underwent thoracotomy, the pericardium was opened, and a silk suture was placed around the left descending coronary artery; ischemia was induced by tightening the suture and was monitored for 30 min. Subsequently, the ligature was released to allow reperfusion lasting for 60 min. The first group of rats was sham operated and injected intraperitoneally (i.p.) with saline. The second group underwent FIR. The third group was treated ip 18 hr before FIR with hemin (4 mg/kg). The fourth group was pretreated ip 24 hr before FIR and 6 hr before hemin with zinc protoporphyrin IX (ZnPP-IX, 50 microg/kg). Specimens of the left ventricle were taken for determination of HO expression and activity, infarct size, malonyldialdehyde (MDA) production, and tissue calcium content. FIR led to a significant increase in the generation of MDA and notably raised tissue calcium levels. Induction of HO-1 by hemin significantly decreased infarct size, incidence of reperfusion arrhythmias, MDA generation, and calcium overload induced by FIR. These effects were prevented by the HO-1 inhibitor ZnPP-IX. The present experiments show that the concerted actions of CO, iron, and biliverdin/bilirubin modulate the FIR-induced myocardial injury.

Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium

“…1B). A significant body of evidence now suggests that enhanced transcription of the HIF-1-driven genes HO-1 and iNOS in myocardium significantly reduce postischemic cardiac injury (28,31,43,47). Our results show that HIF-1 activation significantly increased HO-1 and iNOS gene and protein expression in HL-1 cardiomyocytes (Fig.…”

Mammal Cells Double Their Total RNAs against Diabetes, Ischemia Reperfusion and Malaria-Induced Oxidative Stress

“…Heme or glucose pretreatment 24 hours before diabetes/IR/ malaria could double total cellular RNAs and subsequently alleviate oxidative damages significantly. Similar roles of hepatocellular glycogen in alleviation of liver IR injury (49) and heme in alleviation of heart IR injury (50) have been reported before, although they did not consider the role of cellular RNA amplification. When a cell encounters oxidative stress (such as high glucose or free heme to mammal cells), heme and glucose generate multiple signals to enhance all RNAs (coarse regulation) and prompt anti-stress gene expression simultaneously (fine regulation, Figure SM-8).…”

Pharmacological and Clinical Aspects of Heme Oxygenase

“…Pharmacological induction of HO-1 significantly reduces infarct size and the incidence of reperfusion arrhythmias after myocardial ischemia-reperfusion whereas cardiac tissue damage is exacerbated by HO inhibitors Hangaishi et al, 2000;Masini et al, 2003). The products of increased HO activity are protective in rodent models of ischemiareperfusion injury, allograft and xenograft survival, intimal hyperplasia after balloon injury, or chronic graft rejection (Otterbein et al, 2003).…”