HO-1 and Myocardial Infarction

Pharmacological induction of HO-1 significantly attenuates infarct size and the incidence of reperfusion arrythmias following ischemia/reperfusion, while HO inhibition aggravates cardiac tissue damage. Studies in transgenic animals also confirm the importance of HO-1 in ischemic cardiac injury. Hearts from heterozygous HO-1 knockout mice are more prone to ischemia-reperfusion injury, whereas animals with cardiac-specific HO-1 overexpression suffer less damage. A maladaptive response consisting of increased ventricular dilation, infarction, and thrombosis has also been reported in HO-1-deficient mice during chronic hypoxia. Overexpression of the transgenic HO-1 prevents long-term pathologic tissue remodeling and normalizes tissue function. Moreover, the improvement in cardiac function is accompanied by decreases in oxidative stress, inflammation, and interstitial fibrosis.

Both bilirubin and CO contribute to the protective actions of HO-1 in the heart. Exogenously administered bilirubin significantly improves cardiac function and decreases myocardial infarct size and mitochondrial damage upon reperfusion insult. Similarly, treatment of isolated cardiac cells or hearts with a CO-releasing molecule preserves cell viability and myocardial performance against hyperoxia-reoxygenation damage. In addition, administration of a CO-releasing agent at the time of reperfusion reduces infarct size in a murine model of coronary occlusion. Interestingly, brief exposure to CO produces sustained, long-term cardioprotection that mimics the late phase of ischemic preconditioning.