Oxidative Stress-Mediated Atherosclerosis: Mechanisms and Therapies

Abstract

Atherogenesis, the formation of atherosclerotic plaques, is a complex process that involves several mechanisms, including endothelial dysfunction, neovascularization, vascular proliferation, apoptosis, matrix degradation, inflammation, and thrombosis. The pathogenesis and progression of atherosclerosis are explained differently by different scholars. One of the most common theories is the destruction of well-balanced homeostatic mechanisms, which incurs the oxidative stress. And oxidative stress is widely regarded as the redox status realized when an imbalance exists between antioxidant capability and activity species including reactive oxygen (ROS), nitrogen (RNS) and halogen species, non-radical as well as free radical species. This occurrence results in cell injury due to direct oxidation of cellular protein, lipid, and DNA or via cell death signaling pathways responsible for accelerating atherogenesis. This paper discusses inflammation, mitochondria, autophagy, apoptosis, and epigenetics as they induce oxidative stress in atherosclerosis, as well as various treatments for antioxidative stress that may prevent atherosclerosis.

Keywords: apoptosis; atherosclerosis; autophagy; epigenetics; inflammation; mitochondria; oxidative stress; therapies.

Figure 1

Reactive oxygen species–producing systems in atherosclerosis. MIT oxidative, Mitochondrial oxidative; eNOS, endothelial nitric oxide synthase; ${\text{O}}_2^{•-}$, superoxide; OX, xanthine oxidase; NO^•, nitric oxide; HOCl, hypochlorite; H₂O₂, hydrogen peroxide; ONOO⁻, peroxynitrite; ^•OH, hydroxyl radicals; SOD, enzyme superoxide dismutase; GSH, glutathione; Trx, thioredoxin. ${\text{O}}_2^{•-}$ can be generated in the blood vessel wall by NOXs, uncoupled eNOS, OX, and mitochondrial respiration chains. H₂O₂ can traverse spontaneous transformation to ^•OH by Fe reaction, SOD. H₂O₂ can be detoxified through GSH peroxidase, Trx peroxidase, and catalase to H₂O and O₂. Meanwhile, the myeloperoxidase enzyme can employ H₂O₂ to oxygenize chloride to the strong oxidizer HOCl. The uncoupling eNOS decreases endothelial NO production, which is further aggravated by reduced eNOS expression and activity.

Figure 2

Inflammation, mitochondria, autophagy, apoptosis, and epigenetics-induced oxidative stress during atherosclerosis. ox-LDL, oxidized low-density lipoprotein; ROS, reactive oxygen species; 7-OOH, 7-hydroperoxide; 7-OH, 7-hydroxide; 7 = O, 7-ketone; ATG5, autophagy protein 5; PKCß, protein kinase Cß; ox-HDL, oxidized high-density lipoprotein; ER stress, endoplasmic reticulum stress; TGF-β1, transforming growth factor β1; NOX-4, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase 4; TNF-a, tumor necrosis factors-a; MMP-9, matrix metalloproteinase-9; NLRP3, Nod-like receptor pyrin domain-containing protein 3; MMP-2, matrix metalloproteinase-2; LC3, light chain 3; TLR-9, Toll-like receptor 9; NFE2L2, nuclear translocation of the transcription factor; ATG7, autophagy-related 7; GM–CSF, granulocyte–macrophage colony stimulating factor; Hp2-2, haptoglobin 2-2; Bcl-2 and Bax, apoptotic regulatory proteins; LPC, lysophosphatidylcholine; SOD, superoxide dismutase; Ang II, angiotensin II; ATlR, angiotensin-converting enzyme receptor 1; RBP4, retinol-binding protein 4; MCP-1, monocyte chemotactic protein-1; Hcy, homocysteine; NF-kB, nuclear factor-k-gene binding; Txnip, thioredoxin-interacting protein; NRF-1, nuclear respiratory factor-1; PI3K/AKT, phosphatidylinositol 3 kinase/protein kinase B; Tfam, mitochondrial transcription factor A; MIT dysfunction, mitochondrial dysfunction; mtDNA damage, mitochondrial DNA damage; FGF2, fibroblast growth factor 2; MDA, malondialdehyde.