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• W1978214583 endingPage "H578" @default.
• W1978214583 startingPage "H570" @default.
• W1978214583 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 O 2 -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 O 2 sensing. PASMC mitochondria normally produce reactive O 2 species (ROS) in proportion to Po 2 . Superoxide dismutase 2 (SOD2) converts intramitochondrial superoxide to diffusible H 2 O 2 , which serves as a redox-signaling molecule, regulating pulmonary vascular tone and structure through effects on Kv1.5 and transcription factors. O 2 sensing 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 O 2 -sensing pathway contribute to the pathogenesis of PAH and cancer and constitute promising therapeutic targets." @default.
• W1978214583 created "2016-06-24" @default.
• W1978214583 creator A5011075689 @default.
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• W1978214583 creator A5036578095 @default.
• W1978214583 creator A5052491243 @default.
• W1978214583 creator A5083044879 @default.
• W1978214583 date "2008-02-01" @default.
• W1978214583 modified "2023-10-16" @default.
• W1978214583 title "Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1α-Kv1.5 O₂-sensing pathway at the intersection of pulmonary hypertension and cancer" @default.
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