0481 : Potassium channel subfamily K member 3 (KCNK3) contributes to the development of pulmonary arterial hypertension - 05/05/16
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Résumé |
Background |
Mutations in the KCNK3 gene have been identified in some patients suffering from heritable pulmonary arterial hypertension (PAH). KCNK3 encodes for an outward rectifier K+ channel, and each identified mutations lead to a loss of function. However, the pathophysiological role of KCNK3 in PAH remains to be elucidated. We hypothesized that KCNK3 loss of function is a hallmark of idiopathic and heritable PAH and contributes to the pulmonary artery (PA) smooth muscle cells (PASMC) and endothelial cells (PAEC) dysfunction responsible for PA remodelling, and that restoring KCNK3 expression and function would alleviate experimental pulmonary hypertension (PH).
Methods and results |
We demonstrated that KCNK3 expression and function are reduced in human PAH and in monocrotaline (MCT)-induced PH (MCT-PH) in rats. Using Patch-clamp technique in freshly isolated (not cultured) PASMC and PAEC, we showed that KCNK3-current decreases progressively during the development of MCT-PH and correlates to plasma membrane depolarization. We demonstrated that KCNK3 modulates the pulmonary arterial tone. Chronic inhibition of KCNK3 in rat, induced distal neomuscularization and early hemodynamic signs of PH, related to exaggerated proliferation of PAEC, PASMC adventitial fibroblasts and pulmonary and systemic inflammation. Last, in vivo pharmacological activation of KCNK3 reversed significantly MCT-PH in rats.
Conclusions |
In PAH and experimental PH, KCNK3 expression and activity are strongly reduced in PASMC and PAEC. KCNK3 inhibition promotes increased proliferation, vasoconstriction and inflammation. Rescue of KCNK3 expression alleviated MCT-PH demonstrating that loss of KCNK3 is a key event of PAH pathogenesis and could be therapeutically targeted.
The author hereby declares no conflict of interest
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Vol 8 - N° 3
P. 247-248 - avril 2016 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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