Scavenging Mitochondrial ROS by UCP2 Attenuates Atherosclerosis through Suppression of Endoplasmic Reticulum Stress

Atherosclerosis is a global health burden and greatly increases the risk of developing stroke, coronary artery diseases, and myocardial infarction. Oxidative stress in the vascular wall critically contributes to atherogenesis through damaging functions of a wide range of important cellular proteins. Endoplasmic reticulum (ER) stress is an evolutionarily conserved cellular stress response mechanism utilized to cope with accumulated unfolded proteins in the ER. Initial induction of ER stress protects cells from harmful stimuli while sustained or prolonged ER stress leads to cell dysfunction or/and apoptosis. Emerging evidence indicates a potentially important role of chronic ER stress during the development of cardiovascular and metabolic diseases via inducing progressive dysfunction of multiple organs involving complex pathological processes. Recent advances in vascular biology research demonstrate that ER stress in the vascular wall participates in vascular dysfunction manifested by increased endothelial cell injury and inflammation, impaired endothelium-dependent vasodilatations, and accelerated atherogenesis. Mitochondrial ROS is the primary contributor to increased oxidative stress. However, whether scavenging mitochondrial ROS by antioxidant proteins can retard atherogenesis is still unclear and whether endothelial ER stress in part mediates atherogenesis remains to be explored. Moreover, whether inhibition of ER stress at specific branch(s) is beneficial for preserving endothelial function during the development of atherosclerosis needs characterization.Uncoupling protein-2 (UCP2) is a mitochondrial protein and its primary function is to control mitochondrial ROS generation. Our preliminary results show that UCP2 level in human endothelial cells is suppressed by pro-inflammatory cytokines and disturbed shear stress. Although our initial observations clearly suggest the functional significance of endothelial UCP2 in vascular pathophysiology in the context of atherosclerosis, we need to address several important scientific questions concerning molecular mechanisms involved. To this end, by employing mouse models of atherosclerosis (ApeE-/-) and endothelium-specific Ucp2 knockout, we will (1) investigate whether UCP2-regulated mitochondrial ROS plays a causal role in atherogenesis through induction of endoplasmic reticulum stress in vascular endothelial cells; and (2) identify the molecular mediator integrating the crosstalk between mitochondria ROS and ER stress to cause endothelial inflammation and damage, and to investigate whether IRE1α kinase inhibitor KIRA6 inhibits atherosclerosis.In this proposed study, we shall provide the first line of evidence demonstrating a functional importance of UCP2 deficiency-associated mitochondrial ROS over-production in mediating ER dysfunction in atherosclerosis. The identification of key mediator(s) for propagating the organellar signals to nucleus will be useful for deeper understanding of the functional link between mitochondria and ER in controlling endothelial cell function. Furthermore, pharmacological inhibition of the IRE1α branch of ER stress shall provide additional useful venue for the prevention and treatment of atherosclerotic diseases.