Induction of apoptosis and autosis in cardiomyocytes by the combination of homocysteine and copper via NOX-mediated p62 expression

High levels of homocysteine (Hcy) associated with cardiovascular events are accompanied by increased copper (Cu) concentrations in the blood. Hcy has been shown to promote endothelial dysfunction, whereas the effect of Hcy on cardiomyocytes and the role of Cu in the pathogenesis remain less understood. In the present study, it is demonstrated that the combination of Hcy and Cu(2+)-induced apoptosis and autosis of cardiomyocytes simultaneously, and thus led to cardiac dysfunction in hyperhomocysteinemic rats. These effects were associated with p22(phox) activation and NADPH oxidase (NOX)-mediated p62 upregulation. Inhibition of the expression of p22(phox) or p62 in cardiomyocytes significantly attenuated Hcy and Cu(2+)-mediated reactive oxygen species (ROS) generation and cell death. Furthermore, interrupting the NOX–p62 axis prevented diastolic dysfunction in hyperhomocysteinemic rats (HcyR). These findings establish that the induction of apoptosis and autosis of cardiomyocytes through stimulating the NOX–p62-signaling pathway constitutes a novel mechanism of Hcy and Cu-induced cardiac dysfunction.