title: TWIK-2 channel deficiency leads to pulmonary hypertension through a rho-kinase-mediated process.
abstract: TWIK-2 (KCNK6) is a member of the 2-pore domain (K2P) family of potassium channels, which are highly expressed in the vascular system. We tested the hypothesis that TWIK-2 deficiency leads to pulmonary hypertension. TWIK-2 knockout mice and their wildtype littermates at 8 weeks of age had similar mean right ventricular systolic pressures (24±3 and 21±3 mm Hg, respectively.) Significantly, by 20 weeks of age, the mean right ventricular systolic pressures in TWIK-2 knockout mice increased to 35±3 mm Hg (P≤0.036), whereas mean right ventricular systolic pressures in wildtype littermates remained at 22±3 mm Hg. Elevated mean right ventricular systolic pressures in the TWIK-2 knockout mice was accompanied by pulmonary vascular remodeling as determined by a 25% increase in the cross-sectional area of the vessels occupied by the vessel wall. Additionally, secondary branches of the pulmonary artery from 20-week-old TWIK-2 knockout mice showed an enhanced contractile response to U46619 (10(-6) moles/L), a thromboxane A2 mimetic, which was completely abolished with the Rho-kinase inhibitor, Y27632 (10(-6) and 10(-5) moles/L). Treatment of TWIK-2 knockout mice with the Rho-kinase inhibitor, fasudil, in the drinking water for 12 weeks, abolished the development of pulmonary hypertension and attenuated the vessel remodeling. We concluded that mice deficient in the TWIK-2 channel develop pulmonary hypertension between 8 and 20 weeks of age through a mechanism involving Rho-kinase. Our results suggest that downregulation of TWIK-2 in the pulmonary vasculature may be an underlying mechanism in the development of pulmonary hypertension.
authors.affiliation: From the Departments of Internal Medicine (L.M.P., X.H.T.W., R.M.B.), Anesthesiology (E.E.L., R.M.B.), Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics (J.O.R., C.R., X.H.T.W., R.M.B.), Baylor College of Medicine, and Department of Microbiology and Immunology (W.S.L.), The University of Texas Medical Branch lpandit@bcm.edu.
authors.forename: Lavannya M
authors.initials: LM
authors.lastname: Pandit
authors.affiliation: From the Departments of Internal Medicine (L.M.P., X.H.T.W., R.M.B.), Anesthesiology (E.E.L., R.M.B.), Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics (J.O.R., C.R., X.H.T.W., R.M.B.), Baylor College of Medicine, and Department of Microbiology and Immunology (W.S.L.), The University of Texas Medical Branch.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Lloyd
authors.affiliation: From the Departments of Internal Medicine (L.M.P., X.H.T.W., R.M.B.), Anesthesiology (E.E.L., R.M.B.), Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics (J.O.R., C.R., X.H.T.W., R.M.B.), Baylor College of Medicine, and Department of Microbiology and Immunology (W.S.L.), The University of Texas Medical Branch.
authors.forename: Julia O
authors.initials: JO
authors.lastname: Reynolds
authors.affiliation: From the Departments of Internal Medicine (L.M.P., X.H.T.W., R.M.B.), Anesthesiology (E.E.L., R.M.B.), Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics (J.O.R., C.R., X.H.T.W., R.M.B.), Baylor College of Medicine, and Department of Microbiology and Immunology (W.S.L.), The University of Texas Medical Branch.
authors.forename: William S
authors.initials: WS
authors.lastname: Lawrence
authors.affiliation: From the Departments of Internal Medicine (L.M.P., X.H.T.W., R.M.B.), Anesthesiology (E.E.L., R.M.B.), Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics (J.O.R., C.R., X.H.T.W., R.M.B.), Baylor College of Medicine, and Department of Microbiology and Immunology (W.S.L.), The University of Texas Medical Branch.
authors.forename: Corey
authors.initials: C
authors.lastname: Reynolds
authors.affiliation: From the Departments of Internal Medicine (L.M.P., X.H.T.W., R.M.B.), Anesthesiology (E.E.L., R.M.B.), Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics (J.O.R., C.R., X.H.T.W., R.M.B.), Baylor College of Medicine, and Department of Microbiology and Immunology (W.S.L.), The University of Texas Medical Branch.
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.affiliation: From the Departments of Internal Medicine (L.M.P., X.H.T.W., R.M.B.), Anesthesiology (E.E.L., R.M.B.), Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics (J.O.R., C.R., X.H.T.W., R.M.B.), Baylor College of Medicine, and Department of Microbiology and Immunology (W.S.L.), The University of Texas Medical Branch.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Bryan
mesh_terms: D000818:Animals; D001794:Blood Pressure; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005838:Genotype; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024683:Potassium Channels, Tandem Pore Domain / Q000172:deficiency* / Q000235:genetics; D011651:Pulmonary Artery / Q000378:metabolism* / Q000503:physiopathology; D016278:Ventricular Function, Right; D054460:rho-Associated Kinases / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C492208:Kcnk6 protein, mouse; D024683:Potassium Channels, Tandem Pore Domain; D004247:DNA; D054460:rho-Associated Kinases
keywords: KCNK6; Rho-kinase; TWIK-2; potassium channel; pulmonary hypertension