Integrative Physiology Transcriptional Upregulation of Mitochondrial Uncoupling Protein 2 Protects Against Oxidative Stress-Associated Neurogenic Hypertension

Key Words: uncoupling proteins Ⅲ mitochondrion Ⅲ peroxisome proliferator-activated receptor Ⅲ oxidative stress Ⅲ blood pressure L iving organisms possess a variety of physiological protective mechanisms to counteract oxidative stress and to restore redox balance. Oxidative damage to cells that results from an imbalance of production over degradation of the reactive oxygen species (ROS), particularly superoxide anion (O 2 Ϫ⅐) and hydrogen peroxide (H 2 O 2), is associated with a variety of cardiovascular diseases, including heart failure, atherosclerosis, and hypertension. 1–3 Of note is that overproduction of O 2 Ϫ⅐ and H 2 O 2 in the central nervous system contributes to neural mechanisms of hypertension by increasing sympathetic outflow to the peripheral blood vessels. 4,5 In addition to the degradative enzymes (eg, superoxide dismutase [SOD] and catalase) and low-molecular-weight antioxidants (eg, ascorbic acid and glutathione), the uncou-pling proteins (UCPs) have emerged as important natural antioxidants in the maintenance of ROS homeostasis. 6 UCPs belong to a superfamily of mitochondrial anion transporters that uncouple ATP synthesis from oxidative phosphorylation by causing proton leakage across the mitochondrial inner membrane, leading to energy dissipation and heat production. 7 More importantly, the resultant decrease in proton electrochemical gradient across the inner mitochondrial membrane elicited by the UCPs mitigates mitochondrial ROS production. 6,8 In mammals, 5 homologues, UCP1 to UCP5, have so far been cloned. 9 Among them, dysfunction of UCP2 is suggested to be of considerable importance in cardiovas