title: Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis.
abstract: The pulmonary arteries (PA) in pulmonary arterial hypertension (PAH) are constricted and remodeled;. They have suppressed apoptosis, partly attributable to suppression of the bone morphogenetic protein axis and selective downregulation of PA smooth muscle cell (PASMC) voltage-gated K+ channels, including Kv1.5. The Kv downregulation-induced increase in [K+]i, tonically inhibits caspases, further suppressing apoptosis. Mitochondria control apoptosis and produce activated oxygen species like H2O2, which regulate vascular tone by activating K+ channels, but their role in PAH is unknown. We show that dichloroacetate (DCA), a metabolic modulator that increases mitochondrial oxidative phosphorylation, prevents and reverses established monocrotaline-induced PAH (MCT-PAH), significantly improving mortality. Compared with MCT-PAH, DCA-treated rats (80 mg/kg per day in drinking water on day 14 after MCT, studied on day 21) have decreased pulmonary, but not systemic, vascular resistance (63% decrease, P<0.002), PA medial thickness (28% decrease, P<0.0001), and right ventricular hypertrophy (34% decrease, P<0.001). DCA is similarly effective when given at day 1 or day 21 after MCT (studied day 28) but has no effect on normal rats. DCA depolarizes MCT-PAH PASMC mitochondria and causes release of H2O2 and cytochrome c, inducing a 10-fold increase in apoptosis within the PA media (TUNEL and caspase 3 activity) and decreasing proliferation (proliferating-cell nuclear antigen and BrdU assays). Immunoblots, immunohistochemistry, laser-captured microdissection-quantitative reverse-transcription polymerase chain reaction and patch-clamping show that DCA reverses the Kv1.5 downregulation in resistance PAs. In summary, DCA reverses PA remodeling by increasing the mitochondria-dependent apoptosis/proliferation ratio and upregulating Kv1.5 in the media. We identify mitochondria-dependent apoptosis as a potential target for therapy and DCA as an effective and selective treatment for PAH.
authors.affiliation: Department of Medicine and Pediatrics, University of Alberta, Edmonton, Canada.
authors.forename: M Sean
authors.initials: MS
authors.lastname: McMurtry
authors.forename: Sebastien
authors.initials: S
authors.lastname: Bonnet
authors.forename: Xichen
authors.initials: X
authors.lastname: Wu
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Alois
authors.initials: A
authors.lastname: Haromy
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000209:etiology / Q000517:prevention & control; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000473:pathology; D051666:Kv1.5 Potassium Channel; D008928:Mitochondria / Q000187:drug effects; D016686:Monocrotaline / Q000633:toxicity; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000473:pathology; D009928:Organ Specificity; D010085:Oxidative Phosphorylation / Q000187:drug effects; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D051669:Shab Potassium Channels; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: C496983:Kcna5 protein, rat; D051666:Kv1.5 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D051669:Shab Potassium Channels; D016686:Monocrotaline; D003999:Dichloroacetic Acid