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Reactive Oxygen Species (ROS), Intimal Thickening, and Subclinical Atherosclerotic Disease

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Review

Reactive Oxygen Species (ROS), Intimal Thickening, and Subclinical Atherosclerotic Disease

Denise Burtenshaw et al. Front Cardiovasc Med.

Abstract

Arteriosclerosis causes significant morbidity and mortality worldwide. Central to this process is the development of subclinical non-atherosclerotic intimal lesions before the appearance of pathologic intimal thickening and advanced atherosclerotic plaques. Intimal thickening is associated with several risk factors, including oxidative stress due to reactive oxygen species (ROS), inflammatory cytokines and lipid. The main ROS producing systems in-vivo are reduced nicotinamide dinucleotide phosphate (NADPH) oxidase (NOX). ROS effects are context specific. Exogenous ROS induces apoptosis and senescence, whereas intracellular ROS promotes stem cell differentiation, proliferation, and migration. Lineage tracing studies using murine models of subclinical atherosclerosis have revealed the contributory role of medial smooth muscle cells (SMCs), resident vascular stem cells, circulating bone-marrow progenitors and endothelial cells that undergo endothelial-mesenchymal-transition (EndMT). This review will address the putative physiological and patho-physiological roles of ROS in controlling vascular cell fate and ROS contribution to vascular regeneration and disease progression.

Keywords: NAPDH oxidase; NOX; adventitial cells; arteriosclerosis; endothelial cells; intimal thickening; smooth muscle (physiology); stem cells.

Figures

Figure 1
Figure 1
Enzymatic sources of superoxide anion (·O2−). The major enzymes responsible for ROS generation in the vasculature include mitochondria (mtROS), NAD(P)H oxidase, xanthine oxidase, and uncoupled NOS. NAD(P)H oxidase is a multi-subunit enzyme, comprising gp91phox (or its homologs, NOX1 and NOX4), p22phox, p47phox (or NOXO1), p67phox (or NOXA1), and p40phox. Smooth muscle cell (SMC), endothelial cell (EC), Myeloid Cell (monocytes and macrophages), vSC (vascular stem cell). The mitochondrial electron transport chain produces mtROS. Mitochondrial complexes I and II use electrons donated from NADH and FADH2 to reduce coenzyme Q during the process of oxidative phosphorylation (OXPHOS). Leakage of electrons at complex I and complex III from electron transport chains leads to partial reduction of oxygen to form superoxide [Quinol QH2, quinone Q and C cytochrome c].
Figure 2
Figure 2
NADPH oxidase (NOX) activation. NOX comprises cytosolic (p47phox, p67 phox, p40 phox, and Rac) and membrane subunits (gp91 phox and p22 phox). During activation of NOX, cytosolic subunits comprise a multi-component enzyme and mi- grate to the plasma membrane to dock with the membrane subunits. This multi-subunit enzyme produces a superoxide anion (O2·).
Figure 3
Figure 3
NOX enzymes present within the vascular walls. Schematic depicts the repertoire of NOX enzymes within all three layers of the vascular wall, the adventitia (i.e., fibroblasts, macrophages, and adventitial progenitor stem cells), the media (i.e., smooth muscle cells accounting for 90% of the vessel wall) and the intima (i.e., endothelial cells/smooth muscle cells). Although all isoforms are expressed at some levels within all three layers there are distinct NOX profiles associated with each layer. NOX4 is the predominant isoform in endothelial cells, NOX1 and NOX4 in smooth muscle cells, Nox4 in fibroblasts, and Nox2 and NOX4 in resident vascular stem cells.
Figure 4
Figure 4
The role of NOX isoforms in vascular disease progression. Schematic represents the role of NOX 1/4 enzymes in the progression of arteriosclerosis. A healthy artery is depicted with three distinct layers, the outermost layer; the adventitia, the middle layer; the media and the innermost layer; the intima. The activity of NOX 1/4 enzymes and subsequent production of ROS leads to the progression of arteriosclerosis. This is characterized by the accumulation of neointimal SMC-like cells within the medial and intimal layers (intimal medial thickening), an induction of adventitial fibrosis represented by a slight increase out the adventitia, and a distinctive narrowing of the lumen subsequently resulting in restricted blood flow.
Figure 5
Figure 5
The role of NOX isoforms in vascular stem cell populations. Schematic represents the effect of NOX 1,2, and 4 enzymes on stem cell activity within the vasculature. There are two major resident stem cell populations that are effected by NOX enzymes, adventitial Sca1/S100β+ and resident vascular mesenchymal-like stem cells. NOX2 is predominantly associated with hypertensive vessels and promotes the secretion of monocyte chemoattractant protein (MCP-1) and interleukin 6 (IL-6) whilst NOX 1/4 are associated with hypoxic challenge and fibrosis in adventitial progenitor cells. Proliferation, self-renewal and differentiation of resident vascular stem cells is driven by NOX 1,2, and 4 as the production of ROS- mediates P13K/AKT dependent signaling whilst orchestrating a redox-mediated regulatory mechanisms of stem cell function of vascular repair.

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