Author:
Archer Stephen L.,Gomberg-Maitland Mardi,Maitland Michael L.,Rich Stuart,Garcia Joe G. N.,Weir E. Kenneth
Abstract
Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by vascular obstruction and right ventricular failure. Although the fundamental cause remains elusive, many predisposing and disease-modifying abnormalities occur, including endothelial injury/dysfunction, bone morphogenetic protein receptor-2 gene mutations, decreased expression of the O2-sensitive K+channel (Kv1.5), transcription factor activation [hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-activating T cells], de novo expression of survivin, and increased expression/activity of both serotonin transporters and platelet-derived growth factor receptors. Together, these abnormalities create a cancerlike, proliferative, apoptosis-resistant phenotype in pulmonary artery smooth muscle cells (PASMCs). A possible unifying mechanism for PAH comes from studies of fawn-hooded rats, which manifest spontaneous PAH and impaired O2sensing. PASMC mitochondria normally produce reactive O2species (ROS) in proportion to Po2. Superoxide dismutase 2 (SOD2) converts intramitochondrial superoxide to diffusible H2O2, which serves as a redox-signaling molecule, regulating pulmonary vascular tone and structure through effects on Kv1.5 and transcription factors. O2sensing is mediated by this mitochondria-ROS-HIF-1α-Kv1.5 pathway. In PAH and cancer, mitochondrial metabolism and redox signaling are reversibly disordered, creating a pseudohypoxic redox state characterized by normoxic decreases in ROS, a shift from oxidative to glycolytic metabolism and HIF-1α activation. Three newly recognized mitochondrial abnormalities disrupt the mitochondria-ROS-HIF-1α-Kv1.5 pathway: 1) mitochondrial pyruvate dehydrogenase kinase activation, 2) SOD2 deficiency, and 3) fragmentation and/or hyperpolarization of the mitochondrial reticulum. The pyruvate dehydrogenase kinase inhibitor, dichloroacetate, corrects the mitochondrial abnormalities in experimental models of PAH and human cancer, causing a regression of both diseases. Mitochondrial abnormalities that disturb the ROS-HIF-1α-Kv1.5 O2-sensing pathway contribute to the pathogenesis of PAH and cancer and constitute promising therapeutic targets.
Publisher
American Physiological Society
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology
Cited by
317 articles.
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