NADPH Oxidase-4 Driven Cardiac Macrophage Polarization Protects Against Myocardial Infarction-Induced Remodeling.

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.

Involvement of Nox2 NADPH oxidase in adverse cardiac remodeling after myocardial infarction.

Oxidative stress plays an important role in the development of cardiac remodeling after myocardial infarction (MI), but the sources of oxidative stress remain unclear. We investigated the role of Nox2-containing reduced nicotinamide-adenine dinucleotide phosphate oxidase in the development of cardiac remodeling after MI. Adult Nox2(-/-) and matched wild-type (WT) mice were subjected to coronary artery ligation and studied 4 weeks later. Infarct size after MI was similar in Nox2(-/-) and WT mice. Nox2(-/-) mice exhibited significantly less left ventricular (LV) cavity dilatation and dysfunction after MI than WT mice (eg, echocardiographic LV end-diastolic volume: 75.7+/-5.8 versus 112.4+/-12.3 microL; ejection fraction: 41.6+/-3.7 versus 32.9+/-3.2%; both P<0.05). Similarly, in vivo LV systolic and diastolic functions were better preserved in Nox2(-/-) than WT mice (eg, LV dP/dt(max): 7969+/-385 versus 5746+/-234 mm Hg/s; LV end-diastolic pressure: 12.2+/-1.3 versus 18.0+/-1.8 mm Hg; both P<0.05). Nox2(-/-) mice exhibited less cardiomyocyte hypertrophy, apoptosis, and interstitial fibrosis; reduced increases in expression of connective tissue growth factor and procollagen 1 mRNA; and smaller increases in myocardial matrix metalloproteinase-2 activity than WT mice. These data suggest that the Nox2-containing reduced nicotinamide-adenine dinucleotide phosphate oxidase contributes significantly to the processes underlying adverse cardiac remodeling and contractile dysfunction post-MI.

Oxidative stress and redox signalling in cardiac hypertrophy and heart failure.

Substantial evidence suggests the involvement of oxidative stress in the pathophysiology of congestive heart failure and its antecedent conditions such as cardiac hypertrophy and adverse remodelling after MI. Oxidative stress describes an imbalance between antioxidant defences and the production of reactive oxygen species (ROS), which at high levels cause cell damage but at lower levels induce subtle changes in intracellular signalling pathways (termed redox signalling). ROS are derived from many sources including mitochondria, xanthine oxidase, uncoupled nitric oxide synthases and NADPH oxidases. The latter enzymes are especially important in redox signalling, being implicated in the pathophysiology of hypertension and atherosclerosis, and activated by diverse pathologically relevant stimuli. We review the contribution of ROS to heart failure pathophysiology and discuss potential therapies that may specifically target detrimental redox signalling. Indeed, drugs such as ACE inhibitors and statins may act in part through such mechanisms. A better understanding of redox signalling mechanisms may enable the development of new targeted therapeutic strategies rather than the non-specific antioxidant approaches that have to date been disappointing in clinical trials.