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

• Type: Article in International Scientific Journal
• Date: 2021

Authors

Lambert, M (Author) Other; Mendes Ferreira, P (Author) FMUP; Ghigna, MR (Author) Other; LeRibeuz, H (Author) Other; Adao, R (Author) FMUP; Boet, A (Author) Other; Capuano, V (Author) Other; Rucker Martin, C (Author) Other; Brás-Silva C (Author) FMUP; Quarck, R (Author) Other; Domergue, V (Author) Other; Vachiery, JL (Author) Other; Humbert, M (Author) Other; Perros, F (Author) Other; Montani, D (Author) Other; Antigny, F (Author) Other

Journal

Title: Cardiovascular Research

Vol. 117

Pages: 2474-2488

ISSN: 0008-6363

Publisher: Oxford University Press

Indexing

ISI Web of Knowledge - 20 Citations

Scopus - 19 Citations

Other information

Authenticus ID: P-00V-73Q

DOI: 10.1093/cvr/cvab016

Abstract (EN): 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, white 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 welt as pulmonary veins) remodelling with intense pert-vascular and pert-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. [GRAPHICS] .

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 15