Role of heme oxygenase 1 in cardiac ferroptosis in sickle cell disease

Abstract

Decreased red blood cell (RBC) half-life in sickle cell disease (SCD) results in increased hemolysis and is associated with stroke and other cardiovascular complications although the exact mechanisms remain unexplored. We hypothesized that increased circulating heme in SCD promotes cardiotoxicity through ferroptosis by upregulating heme oxygenase 1 (Hmox1). Our data demonstrated that sickling Townes mice had higher serum heme, lower serum levels of the heme scavenger protein hemopexin and increased cardiotoxicity and that supplementation with hemopexin decreased cardiotoxicity in sickling mice. We also demonstrated that cardiac expression of Hmox1 was increased in SCD mice; inhibition or induction of Hmox1 decreased or worsened cardiac damage, respectively. We also demonstrated that labile redox-active iron, a product of heme degradation by Hmox1, was increased in SCD. Subsequently, we evaluated if ferroptosis, an iron-dependent non-apoptotic cell death mechanism, resulted from increased Hmox1 and drove cardiotoxicity in SCD. We found an increase in lipid peroxidation and ferroptotic markers in the cardiac tissue of SCD mice, which were corrected by hemopexin and Hmox1 inhibition whereas Hmox1 induction exacerbated lipid peroxidation and cardiac ferroptosis. Finally, inhibitors or inducers of ferroptosis decreased or exacerbated SCD cardiotoxicity respectively. Together, our results identify a novel mechanism for heme-associated cardiac damage in SCD.