Kcnk3 dysfunction exaggerates the development of pulmonary hypertension induced by left ventricular pressure overload

Cardiovasc Res. 2021 Nov 1;117(12):2474-2488. doi: 10.1093/cvr/cvab016.


Aims: Pulmonary hypertension (PH) is a common complication of left heart disease (LHD, Group 2 PH) leading to right ventricular (RV) failure and death. Several loss-of-function (LOF) mutations in KCNK3 were identified in pulmonary arterial hypertension (PAH, Group 1 PH). Additionally, we found that KCNK3 dysfunction is a hallmark of PAH at pulmonary vascular and RV levels. However, the role of KCNK3 in the pathobiology of PH due to LHD is unknown.

Methods and results: We evaluated the role of KCNK3 on PH induced by ascending aortic constriction (AAC), in WT and Kcnk3-LOF-mutated rats, by echocardiography, RV catheterization, histology analyses, and molecular biology experiments. We found that Kcnk3-LOF-mutation had no consequence on the development of left ventricular (LV) compensated concentric hypertrophy in AAC, while left atrial emptying fraction was impaired in AAC-Kcnk3-mutated rats. AAC-animals (WT and Kcnk3-mutated rats) developed PH secondary to AAC and Kcnk3-mutated rats developed more severe PH than WT. AAC-Kcnk3-mutated rats developed RV and LV fibrosis in association with an increase of Col1a1 mRNA in right ventricle and left ventricle. AAC-Kcnk3-mutated rats developed severe pulmonary vascular (pulmonary artery as well as pulmonary veins) remodelling with intense peri-vascular and peri-bronchial inflammation, perivascular oedema, alveolar wall thickening, and exaggerated lung vascular cell proliferation compared to AAC-WT-rats. Finally, in lung, right ventricle, left ventricle, and left atrium of AAC-Kcnk3-mutated rats, we found a strong increased expression of Il-6 and periostin expression and a reduction of lung Ctnnd1 mRNA (coding for p120 catenin), contributing to the exaggerated pulmonary and heart remodelling and pulmonary vascular oedema in AAC-Kcnk3-mutated rats.

Conclusions: Our results indicate that Kcnk3-LOF is a key event in the pathobiology of PH due to AAC, suggesting that Kcnk3 channel dysfunction could play a potential key role in the development of PH due to LHD.

Keywords: Ascending-aortic constriction; K2P3.1; PH due to left heart diseases; Proliferation; Task-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arterial Pressure*
  • Disease Models, Animal
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Potassium Channels, Tandem Pore Domain / genetics
  • Potassium Channels, Tandem Pore Domain / metabolism*
  • Pulmonary Arterial Hypertension / etiology*
  • Pulmonary Arterial Hypertension / genetics
  • Pulmonary Arterial Hypertension / metabolism
  • Pulmonary Arterial Hypertension / physiopathology
  • Pulmonary Artery / metabolism*
  • Pulmonary Artery / physiopathology
  • Rats
  • Rats, Transgenic
  • Signal Transduction
  • Vascular Remodeling
  • Ventricular Dysfunction, Left / complications*
  • Ventricular Dysfunction, Left / genetics
  • Ventricular Dysfunction, Left / metabolism
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Function, Left*
  • Ventricular Pressure


  • Nerve Tissue Proteins
  • Potassium Channels, Tandem Pore Domain
  • potassium channel subfamily K member 3