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Heme oxygenase-1 and the ischemia-reperfusion injury in the rat heart
Emanuela Masini1, A Vannacci, C Marzocca
1Departments of Preclinical and Clinical Pharmacology, University of Florence, 50139, Florence, Italy. emanuela.masini@unifi.it
Insights
Carbon monoxide (CO) protects the heart from injury during focal ischemia-reperfusion (FIR) by modulating heme oxygenase-1 (HO-1) activity. This signaling gas reduces infarct size and arrhythmias, offering a potential therapeutic target for cardiac events.
Area of Science:
- Cardiovascular Research
- Biochemistry
- Cellular Signaling
Background:
- Carbon monoxide (CO) is an endogenous gasotransmitter produced by heme oxygenase (HO) enzymes.
- HO-1 and HO-2 catalyze heme breakdown, releasing CO, biliverdin, and iron.
- The role of the HO-1 system in myocardial focal ischemia-reperfusion (FIR) injury requires further investigation.
Purpose of the Study:
- To investigate the effects of manipulating the HO-1 system on in vivo rat heart FIR injury.
- To determine the impact of HO-1 induction and inhibition on cardiac damage markers.
Main Methods:
- Male Wistar albino rats underwent 30 min of left descending coronary artery occlusion followed by 60 min of reperfusion (FIR).
- Groups included sham operation, FIR, FIR with hemin (HO-1 inducer), and FIR with hemin plus zinc protoporphyrin IX (ZnPP-IX, HO-1 inhibitor).
- Measurements included HO expression/activity, infarct size, malonyldialdehyde (MDA), and tissue calcium content.
Main Results:
- FIR significantly increased MDA generation and tissue calcium levels.
- Hemin-induced HO-1 significantly decreased infarct size, reperfusion arrhythmias, MDA, and calcium overload.
- The protective effects of hemin were abolished by the HO-1 inhibitor ZnPP-IX.
Conclusions:
- HO-1 induction by hemin confers significant protection against FIR-induced myocardial injury.
- CO, iron, and biliverdin/bilirubin produced by HO-1 modulate cardiac damage during FIR.
- Targeting the HO-1 system presents a potential therapeutic strategy for myocardial ischemia-reperfusion injury.
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.
