Loss of KCNK3 is a hallmark of RV hypertrophy/dysfunction associated with pulmonary hypertension

Mélanie Lambert, Angèle Boet, Catherine Rucker-Martin, Pedro Mendes-Ferreira, Véronique Capuano, Stéphane Hatem, Rui Adão, Carmen Brás-Silva, Aurélie Hautefort, Jean Baptiste Michel, Peter Dorfmuller, Elie Fadel, Tom Kotsimbos, Laura Price, Philippe Jourdon, David Montani, Marc Humbert, Frédéric Perros, Fabrice Antigny

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22 Citations (Scopus)

Abstract

Aims Mutations in the KCNK3 gene, which encodes for an outward-rectifier K+ channel, have been identified in patients suffering from pulmonary arterial hypertension (PAH), and constitute the first described channelopathy in PAH. In human PAH and experimental pulmonary hypertension (PH), we demonstrated that KCNK3 expression and function are severely reduced in pulmonary vascular cells, promoting PH-like phenotype at the morphologic and haemodynamic levels. Since KCNK3 channel is also expressed in both the human and rodent heart, we aimed to elucidate the pathophysiological role of KCNK3 channel in right ventricular (RV) hypertrophy (RVH) related to PH. Methods and results Using whole-cell Patch-clamp technique, we demonstrated that KCNK3 is predominantly expressed in adult rat RV cardiomyocytes compared to the left ventricle cardiomyocytes and participates in the repolarizing phase of the RV action potential. We revealed a reduction in KCNK3 function prior to development of RVH and the rise of pulmonary vascular resistance. KCNK3 function is severely reduced in RV cardiomyocytes during the development of RVH in several rat models of PH (exposure to monocrotaline, chronic hypoxia, and Sugen/hypoxia) and chronic RV pressure overload (pulmonary artery banding). In experimental PH, we revealed a reduction in KCNK3 function before any rise in pulmonary vascular resistance and the development of RVH. KCNK3 mRNA level is also reduced in human RV tissues from PAH patients compared to non-PAH patients. In line with these findings, chronic inhibition of KCNK3 in rats with the specific inhibitor (A293) induces RV hypertrophy which is associated with the reexpression of foetal genes, RV fibrosis, RV inflammation, and subsequent loss of RV performance as assessed by echocardiography. Conclusion Our data indicate that loss of KCNK3 function and expression is a hallmark of the RV hypertrophy/dysfunction associated with PH.

Original languageEnglish
Pages (from-to)880-893
Number of pages14
JournalCardiovascular Research
Volume114
Issue number6
DOIs
Publication statusPublished - 1 May 2018

Keywords

  • A293
  • Ito
  • K2P3.1
  • KCNK3 inhibitor
  • MCT
  • RV dysfunction
  • TASK-1

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