Unbalanced Redox With Autophagy in Cardiovascular Disease

Abstract

Precise redox balance is essential for the optimum health and physiological function of the human body. Furthermore, an unbalanced redox state is widely believed to be part of numerous diseases, ultimately resulting in death. In this review, we discuss the relationship between redox balance and cardiovascular disease (CVD). In various animal models, excessive oxidative stress has been associated with increased atherosclerotic plaque formation, which is linked to the inflammation status of several cell types. However, various antioxidants can defend against reactive oxidative stress, which is associated with an increased risk of CVD and mortality. The different cardiovascular effects of these antioxidants are presumably due to alterations in the multiple pathways that have been mechanistically linked to accelerated atherosclerotic plaque formation, macrophage activation, and endothelial dysfunction in animal models of CVD, as well as in in vitro cell culture systems. Autophagy is a regulated cell survival mechanism that removes dysfunctional or damaged cellular organelles and recycles the nutrients for the generation of energy. Furthermore, in response to atherogenic stress, such as the generation of reactive oxygen species, oxidized lipids, and inflammatory signaling between cells, autophagy protects against plaque formation. In this review, we characterize the broad spectrum of oxidative stress that influences CVD, summarize the role of autophagy in the content of redox balance-associated pathways in atherosclerosis, and discuss potential therapeutic approaches to target CVD by stimulating autophagy.

Keywords: Antioxidants; Autophagy; Cardiovascular disease; Inflammation; Oxidative stress.

Fig. 1. Schematic overview of the role of oxidative stress in atherosclerosis.

Atherosclerosis is the progressive narrowing of the arteries due to plaque formation and is considered the major cause of cardiovascular disease. Oxidative stress is a major stressor that affects the development of atherosclerosis, including lipid oxidation, endothelial activation, macrophage foam cell formation, and inflammation. ROS, reactive oxygen species; LDL, low-density lipoprotein; EC, endothelial cell; VSMC, vascular smooth muscle cell; oxLDL, oxidized low-density lipoprotein; mtDNA, mitochondrial DNA; SMC, smooth muscle cell.

Fig. 2. NOX and mitochondria proton transport are major sources of ROS.

NOX and mitochondrial proton transport are major sources of ROS. Because ROS control is crucial for survival, organelles have various antioxidant enzymes to scavenge ROS. NOX, nicotinamide adenine dinucleotide phosphate oxidase; ROS, reactive oxygen species; SOD, superoxide dismutase; Gpx, glutathione peroxidase; Prdx, peroxiredoxins; NADPH, nicotinamide adenine dinucleotide phosphate; NADH, nicotinamide adenine dinucleotide (NAD⁺) hydrogen (H); NAD⁺, nicotinamide adenine dinucleotide; FADH₂, dihydroflavine-adenine dinucleotide; FAD, flavin adenine dinucleotide; ADP, adenosine diphosphate; ATP, adenosine triphosphate.

Fig. 3. Effects of impaired autophagy and potential mechanisms affecting CVD.

Excessive oxidative stress impairs autophagy and could affect CVD through these pathogenetic mechanisms. CVD, cardiovascular disease; VSMC, vascular smooth muscle cell; ECM, extracellular matrix.