Nox4 NADPH Oxidase‐dependent Mitochondrial Oxidative Stress Promotes Cardiovascular Disease in Aging

Abstract

We examined the interplay of aging, oxidative stress (OS) and cardiovascular disease (CVD) using mouse models of OS. We recently reported that prolonged mitochondrial OS in aged SOD2+/− mice causes aortic stiffness and cardiac dysfunction by inducing aortic smooth muscle cell (SMC) stiffness, apoptosis and wall remodeling. We now report that aged apoE−/−/SOD2+/− had significantly increased aortic stiffening and atherosclerosis, and vascular mitochondrial reactive oxygen species (mtROS) and aortic SMC apoptosis compared with aged apoE−/− and young apoE−/−/SOD2+/− mice. In contrast to the effect in young, Nox1/Nox2 NADPH oxidase inhibition failed to attenuate atherosclerosis in aged apoE−/−/p47phox−/− mice. The lack of protection is correlated with increase in ROS and Nox4 expression in VSMC and aortas of aged mice as well as increased mtROS in VSMC. Aged apoE−/− and apoE−/−/p47phox−/− mice also had impaired vascular and cardiac function. Increased Nox4 expression in VSMC of aged mice is associated with increased mitochondrial dysfunction and mtDNA damage and suppression of Nox4 in VSMC attenuated mtROS levels. Nox4 expression also increased with age in both human aortic SMC and carotid arteries and is correlated with human atherosclerotic lesion severity. These data indicate that Nox4‐dependent mitochondrial OS plays a critical role in age‐associated increase in mitochondrial ROS, dysfunction and CVD.