Key result
Kcnk3-LOF-mutated rats developed more severe pulmonary hypertension, exaggerated pulmonary vascular remodeling, and cardiac fibrosis compared to wild-type rats following ascending aortic constriction.
Why the study?
Although KCNK3 loss-of-function mutations are linked to pulmonary arterial hypertension, the role of KCNK3 in the pathobiology of pulmonary hypertension due to left heart disease was unknown.
Does Kcnk3 loss-of-function exacerbate pulmonary hypertension and cardiopulmonary remodeling induced by left ventricular pressure overload in rats?
Does Kcnk3 loss-of-function exacerbate pulmonary hypertension and cardiopulmonary remodeling induced by left ventricular pressure overload in rats?
Kcnk3 loss-of-function exacerbates pulmonary hypertension and cardiopulmonary remodeling induced by left ventricular pressure overload in a rat model, suggesting Kcnk3 channel dysfunction plays a key role in Group 2 PH.
KCNK3 role in Group 2 PH remains unclear; leaves open whether targeting it benefits LHD-associated PH.
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.
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Lambert et al. (2021) studied Pulmonary hypertension due to left heart disease. Kcnk3 loss-of-function mutation vs. Wild-type (WT) rats was evaluated on Development and severity of pulmonary hypertension, cardiac and pulmonary vascular remodeling. Kcnk3-LOF-mutated rats developed more severe pulmonary hypertension, exaggerated pulmonary vascular remodeling, and cardiac fibrosis compared to wild-type rats following ascending aortic constriction.
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