Physiological and pathological functions of NADPH oxidases during myocardial ischemia-reperfusion.

Oxidative stress, the presence of reactive oxygen species (ROS) in excess of the antioxidant capacity in the heart induces myocardial damage, accumulation of which leads to ischemic heart disease and heart failure. NADPH oxidase (Nox) 2 and 4 are the major sources of O2- and H2O2 in the heart and play a crucial role in the regulation of growth and death in cardiomyocytes. Both Nox2 and Nox4 are upregulated in response to ischemia-reperfusion (I/R), thereby contributing to ROS production and consequent myocardial injury. Suppression of either one of them can reduce ROS and I/R injury in the heart. Importantly, however, a minimum level of ROS production by either Nox2 or Nox4 is essential for the activation of HIF-1α and inhibition of PPARα during I/R, such that combined suppression of both Nox2 and Nox4 exacerbates myocardial I/R injury. Thus, either excessive activation or suppression of Noxs below physiological levels can induce cardiac injury. Here we discuss both detrimental and salutary functions of Nox isoforms during myocardial I/R.