Abstract 17279: Kcnk3 Dysfunction Contributes to the Development of Pulmonary Arterial Hypertension - Characterization of Kcnk3 Deficient Rats

• Published in: Circulation (New York, N.Y.) N.Y.), 2016-11, Vol.134 (Suppl_1 Suppl 1), p.A17279-A17279
• Main Authors: Antigny, Fabrice, Lambert, Mélanie, Hautefort, Aurélie, Manoury, Boris, Jourdon, Philippe, Rucker-Martin, Catherine, Girerd, Barbara, Simonnneau, Gérald, Montani, David, Humbert, Marc, Perros, Frédéric
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539

BackgroundInactivating mutations in the KCNK3 gene (K channel) have been identified in heritable forms of pulmonary arterial hypertension (PAH). We discovered that KCNK3 dysfunction contributes actually to the development of both heritable and non-heritable PAH, and to experimental pulmonary hypertension (PH) (Antigny et al. Circulation 2016).Methods and resultsWe generated Kcnk3 deficient rats using CRISPR-Cas9 technology and characterized at electrophysiological, hemodynamics, morphological and molecular levels the first genetically modified rat model linked to kcnk3 mutationKcnk3 (94pb deletion in exon 1 of Kcnk3 gene). Using a patch-clamp technique in freshly isolated pulmonary artery smooth muscle cells (PASMCs), we found that KCNK3-current is absent in heterozygous and homozygous Kcnk3 mutated rats and that isolated PASMC are significantly depolarized compared to WT rats. Kcnk3 mutation induced distal neomuscularization, abnormal pulmonary arteries vasoreactivity, elevated mean right ventricular systolic pressures and upregulation of MAP kinase signaling pathways. Heterozygous Kcnk3-mutated rats developed more severe pulmonary hypertension than WT littermate under hypoxic condition.ConclusionsIn this study we established the first Kcnk3 deficient rat model. We demonstrated that a genetic inactivation of KCNK3 in rats promoted the early signs of pulmonary hypertension, confirming that KCNK3 loss of function is a key event in PAH pathogenesis. The development and characterization of the first Kcnk3 deficient PH-rats model open new opportunities for testing relevant therapeutics molecules in context of heritable PH.