Heme oxygenase-1 induction protects the heart and modulates cellular and extracellular remodelling after myocardial infarction in rats

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme, which regulates cell proliferation and has potential antifibrogenic properties. In the present study, we investigated the effects of pre-emptive HO-1 induction by cobalt protoporphyrin IX on the healing of myocardial infarction in rats. The proliferation and repair of cardiac cells was assessed by immunostaining of Ki67 and proliferating cell nuclear antigen, and apoptosis of cardiomyocytes by terminal deoxynucleotidyl transferase dUTP nick end labelling. Compared with control hearts, HO-1 induction reduced apoptosis and increased proliferation and repair of cardiomyocytes in the infarct border area during the first few days after infarction. Concomitantly, HO-1 decreased accumulation and proliferation of fibroblasts, and down-regulated procollagen type I expression in the infarct area. Furthermore, HO-1 increased expression of the anti-inflammatory cytokine, transforming growth factor-beta 1, suggesting that the cardioprotective effect of HO-1 in the early phase of infarct healing may result partly from the suppression of the inflammatory response. In the remote myocardium, HO-1 inhibited both proliferation and apoptosis of cardiomyocytes, attenuated heart failure-induced increase in the repair of cardiomyocytes and decreased perivascular fibrosis, thereby potentially alleviating adverse ventricular remodelling. The cardioprotective effects of HO-1 in the late phase of infarct healing may be mediated partly by down-regulation of the profibrotic connective tissue growth factor (CTGF), as HO-1 decreased CTGF expression at week 4. In conclusion, our findings suggest an important role for HO-1 in maintaining cellular homeostasis in the postinfarction heart. Modulation of the HO-1 pathway may provide a new therapeutic approach to enhance the recovery of myocardial infarction and protect against pathological myocardial changes.