Oxidative Stress and Endoplasmic Reticular Stress Interplay in the Vasculopathy of Hypertension

Abstract

Under physiologic conditions, reactive oxygen species (ROS) function as signalling molecules that control cell function. However, in pathologic conditions, increased generation of ROS triggers oxidative stress, which plays a role in vascular changes associated with hypertension, including endothelial dysfunction, vascular reactivity, and arterial remodelling (termed the vasculopathy of hypertension). The major source of ROS in the vascular system is NADPH oxidase (NOX). Increased NOX activity drives vascular oxidative stress in hypertension. Molecular mechanisms underlying vascular damage in hypertension include activation of redox-sensitive signalling pathways, post-translational modification of proteins, and oxidative damage of DNA and cytoplasmic proteins. In addition, oxidative stress leads to accumulation of proteins in the endoplasmic reticulum (ER) (termed ER stress), with consequent activation of the unfolded protein response (UPR). ER stress is emerging as a potential player in hypertension as abnormal protein folding in the ER leads to oxidative stress and dysregulated activation of the UPR promotes inflammation and injury in vascular and cardiac cells. In addition, the ER engages in crosstalk with exogenous sources of ROS, such as mitochondria and NOX, which can amplify redox processes. Here we provide an update of the role of ROS and NOX in hypertension and discuss novel concepts on the interplay between oxidative stress and ER stress.