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Carbon monoxide (CO), produced by heme oxygenase-1 (HO-1), is an endogenous paracrine factor involved in the regulation of cardiovascular structure and function. We studied the effects of a synthetic CO releasing molecule (CORM-3) on cardiac recovery and myocardial microRNA expression after myocardial infarction (MI).Male Wistar rats with MI (n = 75) or sham-operated controls (n = 75) were treated from day 4 to day 14 after MI either with synthetic CORM-3 or with inactive iCORM and killed 2, 4 or 8 weeks post-MI. Infarct size, vascular and capillary densities, the amount of cardiomyocytes in the infarct area, and cardiomyocyte proliferation and apoptosis were determined. PCR was used for microRNA and mRNA quantification, western blotting to evaluate protein expression and echocardiography to assess cardiac structure and function.CORM-3 treatment increased vascular density (P< 0.05 vs. iCORM) and the proportion of cardiomyocytes (P< 0.05 vs. iCORM) in the infarct area. Ejection fraction improved (P< 0.05) and left ventricular volumes decreased (P< 0.05) in CORM-3 treated MI groups compared to iCORM treatment. CORM-3 treatment decreased the amount of proliferating Ki67 positive cardiomyocytes in the infarct/border area at week 2 after MI compared to iCORM treatment, whereas the amount of apoptotic cardiomyocytes did not differ between CORM-3 and iCORM groups. Compared to iCORM treatment, CORM-3 decreased expression on miR-206 in the remote area at week 2 after MI.The CO releasing molecule CORM-3 improved structural and functional cardiac recovery after MI. Modulation of HO-1-CO axis may prove novel drug targets to facilitate cardiac recovery after myocardial injury.