Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension

International audienceBackground Mutations in the KCNK3 gene have been identified in some patients suffering from heritable pulmonary arterial hypertension (PAH). KCNK3 encodes an outward rectifier K+ channel, and each identified mutation leads to a loss of function. However, the pathophysiological role of potassium channel subfamily K member 3 (KCNK3) in PAH is unclear. We hypothesized that loss of function of KCNK3 is a hallmark of idiopathic and heritable PAH and contributes to dysfunction of pulmonary artery smooth muscle cells and pulmonary artery endothelial cells, leading to pulmonary artery remodeling: consequently, restoring KCNK3 function could alleviate experimental pulmonary hypertension (PH). Methods and Results We demonstrated that KCNK3 expression and function were reduced in human PAH and in monocrotaline-induced PH in rats. Using a patch-clamp technique in freshly isolated (not cultured) pulmonary artery smooth muscle cells and pulmonary artery endothelial cells, we found that KCNK3 current decreased progressively during the development of monocrotaline-induced PH and correlated with plasma-membrane depolarization. We demonstrated that KCNK3 modulated pulmonary arterial tone. Long-term inhibition of KCNK3 in rats induced distal neomuscularization and early hemodynamic signs of PH, which were related to exaggerated proliferation of pulmonary artery endothelial cells, pulmonary artery smooth muscle cell, adventitial fibroblasts, and pulmonary and systemic inflammation. Lastly, in vivo pharmacological activation of KCNK3 significantly reversed monocrotaline-induced PH in rats. Conclusions In PAH and experimental PH, KCNK3 expression and activity are strongly reduced in pulmonary artery smooth muscle cells and endothelial cells. KCNK3 inhibition promoted increased proliferation, vasoconstriction, and inflammation. In vivo pharmacological activation of KCNK3 alleviated monocrotaline-induced PH, thus demonstrating that loss of KCNK3 is a key event in PAH pathogenesis and thus could be therapeutically targeted

La logistisation du monde

Moins médiatisée que la révolution digitale, une autre révolution, plus discrète et pourtant tout aussi bouleversante pour notre monde, s’est opérée au cours des dernières décennies : celle de la logistique. L’ouvrage revient sur cette « logistisation » du monde, à travers 56 chroniques. Destinées à un grand public, elles ont été écrites par des chercheurs du CRET-LOG, qui constitue le principal centre de recherche en logistique en France. Rédigées dans un langage clair, ces courtes chroniques donnent au lecteur les clefs pour comprendre de manière globale et systémique la révolution logistique. Les chroniques sont réunies en huit parties, qui couvrent tout le spectre de la logistique contemporaine : son omniprésence et son universalité son rôle stratégique pour les entreprises sa place de support à la consommation l’industrie logistique qui la sous-tend la façon dont elle crée de la valeur son rôle de levier vers un développement plus durable les enjeux politiques de la logistique les liens industrie-recherche en logistique. L’ouvrage a l’ambition de médiatiser et diffuser largement la pensée logistique auprès du grand public et intéressera tous ceux qui veulent comprendre les évolutions de notre monde