KCNK3 channel inactivation leads to pulmonary vascular alterations in rat
M. Lambert (Le plessis Robinson, France), V. Capuano (Le plessis Robinson, France), A. Boet (Le plessis Robinson, France), A. Hautefort (Le plessis Robinson, France), T. Bertero (Nice, France), B. Manoury (Chatenay Malabry, France), D. Montani (Le plessis Robinson, France), M. Humbert (Le plessis Robinson, France), F. Perros (Le plessis Robinson, France), F. Antigny (Le plessis Robinson, France)
Source: International Congress 2018 – Pathobiology of pulmonary hypertension
Session: Pathobiology of pulmonary hypertension
Session type: Poster Discussion
Number: 3924
Disease area: Pulmonary vascular diseases
Abstract INTRODUCTION -Mutations in the KCNK3 gene, which encodes for an outward rectifier K+ channel, have been identified in Pulmonary Arterial Hypertension (PAH) patients. Each identified mutations leads to a loss of KCNK3 function.
AIMS AND OBJECTIVES -KCNK3 is not functional in mouse PASMCs, to decipher cellular mechanisms associated with a loss of KCNK3 function in PAH, we generated a transgenic rat line.
METHODS -Using CRSPR/Cas9 technology, we induced a 94pb deletion in exon 1 of Kcnk3 gene. Then, we characterized these rats at electrophysiological, echocardiographic, hemodynamic, morphological and molecular levels.
RESULTS -Using patch-clamp technique we validated our strategy, by demonstrating the absence of KCNK3 current in freshly isolated PASMC from heterozygous and homozygous Kcnk3-deficient rats. At 3 month-old of age, echocardiography revealed a shortening of the pulmonary artery acceleration time associated with an elevation of right ventricular systolic pressures. Moreover, Kcnk3-deficiency induced lung distal neomuscularization, upregulation of MAP kinase (ERK, P-38) and anti-apoptotic (SRC, Survivin) signaling pathways, pulmonary arteries collagen deposition and severe alteration of pulmonary arteries reactivity (contraction/relaxation). Kcnk3-deficient rats developed more severe PH than WT after monocrotaline-exposure. Finally, Kcnk3-deficient rats developed an age-dependent PH.
CONCLUSIONS -In this study we established the first Kcnk3-deficient rat model of PH. Those results confirm that KCNK3 loss of function is a key event in PAH pathogenesis. This model opens new opportunities for understanding initiating mechanisms of PH and testing biologically relevant therapeutic molecules in the context of PH.
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M. Lambert (Le plessis Robinson, France), V. Capuano (Le plessis Robinson, France), A. Boet (Le plessis Robinson, France), A. Hautefort (Le plessis Robinson, France), T. Bertero (Nice, France), B. Manoury (Chatenay Malabry, France), D. Montani (Le plessis Robinson, France), M. Humbert (Le plessis Robinson, France), F. Perros (Le plessis Robinson, France), F. Antigny (Le plessis Robinson, France). KCNK3 channel inactivation leads to pulmonary vascular alterations in rat. 3924
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