Clarity on the Isoform-Specific Roles of NADPH Oxidases and NADPH Oxidase-4 in Atherosclerosis

Atherosclerosis is a complex disease that remains a leading cause of death and disability. The formation of vascular plaques arises from the interaction of dyslipidemia with the altered function of blood vessels and immune cells. The exact cause of atherosclerosis is not known, but from the 1950s onward, oxidative modifications of lipids and proteins were detected in vascular lesions, and the degree of oxidation was found to correlate with the severity of disease.1 Based on these findings, a logical hypothesis emerged that suppression of these oxidative modifications might prevent atherosclerosis. Based on promising preclinical data, antioxidant therapies, which use a broad spectrum approach to suppress the actions of many oxidants, were introduced with much promise for the treatment of atherosclerosis, as well as cancer and aging. The results of numerous clinical trials have been clear, and broad spectrum antioxidant therapies do not provide protection against atherosclerosis.2,3See accompanying article on page 295 of the February 2016 issue are many sources of reactive oxygen species within atherosclerotic lesions, and one of the most prominent reasons cited for the failure of antioxidant therapies is a lack of specificity.1 A highly specialized and abundant source of reactive oxygen species is the family of transmembrane NADPH-dependent oxidoreductases (Nox enzymes) that synthesize superoxide (O2−). There are 7 …