Oxidative stress, NADPH oxidases, and arteries

Abstract

Atherosclerosis and its major complications - myocardial infarction and stroke - remain major causes of death and disability in the United States and world-wide. Indeed, with dramatic increases in obesity and diabetes mellitus, the prevalence and public health impact of cardiovascular diseases (CVD) will likely remain high. Major advances have been made in development of new therapies to reduce the incidence of atherosclerosis and CVD, in particular for treatment of hypercholesterolemia and hypertension. Oxidative stress is the common mechanistic link for many CVD risk factors. However, only recently have the tools existed to study the interface between oxidative stress and CVD in animal models. The most important source of reactive oxygen species (and hence oxidative stress) in vascular cells are the multiple forms of enzymes nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase). Recently published and emerging studies now clearly establish that: 1) NADPH oxidases are of critical importance in atherosclerosis and hypertension in animal models; 2) given the tissue-specific expression of key components of NADPH oxidase, it may be possible to target vascular oxidative stress for prevention of CVD.

Keywords: Oxidative stress; atherosclerosis; diabetes mellitus; hypertension.

Figure 1

The critical role of NADPH oxidases in atherosclerosis, diabetic atherosclerosis, and hypertension as evident from mouse models, NADPH oxidase inhibitors and human data.

Figure 2

GKT136901, a Nox1/Nox4 oxidase inhibitor, decreased atherosclerosis and attenuated ROS generation, plasma 8-isoprostane levels, and CD44 and hyaluronan expression in atherosclerotic lesions. Reprinted from reference 27, with permission from Journal of Biological Chemistry.

Figure 3

ApoE^−/−/p47phox^−/− express less CD44 in atherosclerotic lesions (A) and have decreased aortic root lesion area compared with ApoE^−/− mice (B). Reprinted from reference 41, with permission from Circulation Research.

Figure 4

Mean arterial pressure is decreased in p47phox^−/− compared with the wild-type mice in response to Ang II infusion: daytime (asleep) A; nighttime (awake) B. Reprinted from reference 44, with permission from Hypertension.