NADPH Oxidases and Their Role in Atherosclerosis

Abstract

The current view on atherosclerosis positions it as a multifactorial disorder that results from the interplay between lipid metabolism disturbances and inflammatory processes. Oxidative stress is proven to be one of the initiating factors in atherosclerosis development, being implicated both in the inflammatory response and in atherogenic modifications of lipoproteins that facilitate lipid accumulation in the arterial wall. The hallmark of oxidative stress is the elevated level of reactive oxygen species (ROS). Correspondingly, the activity of major ROS-generating enzymes, including nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, xanthine oxidases, and cyclooxygenases, is an important element in atherosclerosis development. In particular, the role of NADPH oxidases in atherosclerosis development has become a subject of intensive research. Aberrant activity of NADPH oxidases was shown to be associated with cardiovascular disease in humans. With regard to atherosclerosis, several important pathological components of the disease development, including endothelial dysfunction, inflammation, and vascular remodeling, involve aberrations in NADPH oxidases functioning. In humans, NADPH oxidases are represented by four isoforms expressed in vascular tissues, where they serve as the main source of ROS during atherogenesis. Moreover, recent studies have demonstrated their impact on vascular remodeling processes. Interestingly, one of the NADPH oxidase isoforms, NOX4, was shown to have an atheroprotective effect. Despite the growing evidence of the crucial involvement of NADPH oxidases in atherosclerosis pathogenesis, the available data still remains controversial. In this narrative review, we summarize the current knowledge of the role of NADPH oxidases in atherosclerosis and outline the future directions of research.

Keywords: CAD; NADPH oxidase; ROS; atherosclerosis; oxidative stress.

Figure 1

NOX isoforms expressed in vascular cells. NOX1, NOX2, NOX4, and NOX5 can be found in human vascular wall tissue. NOX1, NOX4, and NOX5 are expressed by vascular smooth muscular cells, while NOX2 and NOX4 are present in the endothelium. Macrophages recruited to the subendothelial cells also express NOX2. Together, these enzymes contribute to reactive oxygen species (ROS) formation in the vascular wall and play an important role in the development of local inflammatory processes.

Figure 2

Role of NOX isoforms in vascular remodeling. Oxidative stress and hypertrophy of aortic media in response to angiotensin II (Ang II) signaling and inflammation are mediated by several isoforms of NOX and together lead to vascular remodeling processes.