The reactive oxygen species-generating enzyme NADPH oxidase 4 (Nox4) is up-regulated in the heart after myocardial infarction (MI). Mice with cardiomyocyte-targeted Nox4 overexpression (TG) displayed increased macrophages in the heart at baseline, with skewing toward an M2 phenotype compared with wild-type controls (WT). After MI, TG mice had a higher proportion of M2 macrophages along with higher survival, decreased cardiac remodeling, and better contractile function than wild-type mice. The post-MI increase in cardiac matrix metalloproteinase-2 activity was substantially blunted in TG mice. These results indicate that cardiomyocyte Nox4 modulates macrophage polarization toward an M2 phenotype, resulting in improved post-MI survival and remodeling, likely through the attenuation of cardiac matrix metalloproteinase-2 activity.
Keywords: I/R, ischemia/reperfusion; IL, interleukin; LAD, left anterior descending coronary artery; LV, left ventricular; MI, myocardial infarction; MMP, matrix metalloproteinase; NADPH oxidase; NF-κB, nuclear factor–κB; Nox, NADPH oxidase; TG, transgenic; WT, wild-type; cardiac; infarction; ischemia; mRNA, messenger ribonucleic acid; macrophage; remodeling.