Reactive Oxygen Species, Endoplasmic Reticulum Stress and Mitochondrial Dysfunction: The Link with Cardiac Arrhythmogenesis

Abstract

Background: Cardiac arrhythmias represent a significant problem globally, leading to cerebrovascular accidents, myocardial infarction, and sudden cardiac death. There is increasing evidence to suggest that increased oxidative stress from reactive oxygen species (ROS), which is elevated in conditions such as diabetes and hypertension, can lead to arrhythmogenesis.Method: A literature review was undertaken to screen for articles that investigated the effects of ROS on cardiac ion channel function, remodeling and arrhythmogenesis.Results: Prolonged endoplasmic reticulum stress is observed in heart failure, leading to increased production of ROS. Mitochondrial ROS, which is elevated in diabetes and hypertension, can stimulate its own production in a positive feedback loop, termed ROS-induced ROS release. Together with activation of mitochondrial inner membrane anion channels, it leads to mitochondrial depolarization. Abnormal function of these organelles can then activate downstream signaling pathways, ultimately culminating in altered function or expression of cardiac ion channels responsible for generating the cardiac action potential (AP). Vascular and cardiac endothelial cells become dysfunctional, leading to altered paracrine signaling to influence the electrophysiology of adjacent cardiomyocytes. All of these changes can in turn produce abnormalities in AP repolarization or conduction, thereby increasing likelihood of triggered activity and reentry.Conclusion: ROS plays a significant role in producing arrhythmic substrate. Therapeutic strategies targeting upstream events include production of a strong reducing environment or the use of pharmacological agents that target organelle-specific proteins and ion channels. These may relieve oxidative stress and in turn prevent arrhythmic complications in patients with diabetes, hypertension, and heart failure.

Cancer antigen-125 and risk of atrial fibrillation: a systematic review and meta-analysis

“…Impaired ventricular function, left atrial remodelling, increased vascular mechanical and oxidative stress,22 a prothrombotic state and overall systemic inflammatory response lead to a significant increase in the production of cytokines such as IL-6, TNF-α, IL-8 and IL-10, which induce release of Ca-125 from the epithelial coelomic cells of the serosal tissues. Although most of the studies included in this meta-analysis showed significantly increased levels of Ca-125 in patients with AF, the actual relationship between Ca-125 and AF remains not entirely clear.…”

Mitochondria-Targeted Antioxidant Mito-Tempo Protects Against Aldosterone-Induced Renal Injury In Vivo

“…The ER is responsible for protein synthesis, folding, and maturation, and participates in Ca 2+ storage, signal transduction, lipid, and glucose metabolism. Abnormalities in these factors could cause unfolding or misfolding of proteins, which accumulate in the ER lumen leading to ERS and the unfolded protein response [28, 29]. ERS has been shown to contribute to Aldo-induced renal injury, while treatment with ERS inhibitors (e.g.…”

Mouse models of atherosclerosis: a historical perspective and recent advances

“…There is therefore a need to elucidate the molecular mechanisms underlying these harmful processes in order to devise ways to prevent them. In recent years, the role of oxidative stress, endoplasmic reticulum stress and mitochondrial dysfunction in promoting neointimal proliferation has been intensively studied [152]. VSMCs, the main component of the neointima, are capable of switching from a quiescent and contractile to a proliferative phenotype [153].…”