Post-Infarction Rescue of Myocardial Function Using Hemin

Abstract

Acute myocardial infarction is a major contributor to heart failure but has yet to be fully addressed through current therapeutic interventions. In experimental models of myocardial infarction, pre-emptive heme oxygenase-1 induction directly reduces oxidative stress and inflammation, while limiting pathological fibrotic remodeling and promoting functional cardioprotection. Heme oxygenase-1 elicits cytoprotection through the catabolism of free heme—the functional group by which oxygen is transported in proteins such as hemoglobin, myoglobin, and cytochromes involved in ATP production—into antioxidant and anti-inflammatory by-products. Whether heme oxygenase-1 induction is effective when initiated post-myocardial infarction and how cardiac heme content is endogenously regulated in response to injury is unclear. Here we show that experimental acute myocardial infarction causes temporal dyssynchrony between left ventricular heme content and heme regulatory enzyme expression. Further, we show that hemin—a potent inducer and substrate of heme oxygenase-1—improves cardiac function in experimental models of acute myocardial infarction in a time-dependent manner. We also show for the first time that hemin is capable of directly increasing human cardiac tissue contractility in vitro (by an apparently calcium-independent mechanism), and explore the therapeutic potential of two novel strategies that could be translated for more rapid/targeted delivery of HMOX1/hemin to the infarcted heart: the encapsulation of hemin into a nanoparticle shell (Niohemin), and the exogenous delivery of functional HMOX1 using a cell-penetrating peptide (HMOX1-CPP). Collectively, the findings presented herein provide fundamental information with which to advance the therapeutic targeting of heme metabolism in the heart.