TWIK-2 channel deficiency leads to pulmonary hypertension through a rho-kinase-mediated process

Lavannya M. Pandit, Eric E. Lloyd, Julia O. Reynolds, William Lawrence, Corey Reynolds, Xander H T Wehrens, Robert M. Bryan

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1260-1265
Number of pages6
JournalHypertension
Volume64
Issue number6
DOIs
StatePublished - 2014
Externally publishedYes

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Keywords

  • KCNK6
  • Potassium channel
  • Pulmonary hypertension
  • Rho-kinase
  • TWIK-2

ASJC Scopus subject areas

  • Internal Medicine
  • Medicine(all)

Cite this

Pandit, L. M., Lloyd, E. E., Reynolds, J. O., Lawrence, W., Reynolds, C., Wehrens, X. H. T., & Bryan, R. M. (2014). TWIK-2 channel deficiency leads to pulmonary hypertension through a rho-kinase-mediated process. Hypertension, 64(6), 1260-1265. https://doi.org/10.1161/HYPERTENSIONAHA.114.03406