Potassium-Channel Subfamily K-Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension
Background—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 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 (PA) smooth-muscle cells (PASMC) and endothelial cells (PAEC), leading to PA 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 (MCT)-induced PH (MCT-PH) in rats. Using a patch-clamp technique in freshly isolated (not cultured) PASMC and PAEC, we found that KCNK3-current decreased progressively during development of MCT-PH and correlated with plasma-membrane depolarization. We demonstrated that KCNK3 modulated pulmonary arterial tone. Chronic inhibition of KCNK3 in rats induced distal neomuscularization and early hemodynamic signs of PH, which were related to exaggerated proliferation of PAEC, PASMC adventitial fibroblasts, and pulmonary and systemic inflammation. Lastly, in vivo pharmacological activation of KCNK3 significantly reversed MCT-PH in rats.
Conclusions—In PAH and experimental PH, KCNK3 expression and activity are strongly reduced in PASMC and PAEC. KCNK3 inhibition promoted increased proliferation, vasoconstriction, and inflammation. Renewed KCNK3 expression alleviated MCT-PH, thus demonstrating that loss of KCNK3 is a key event in PAH pathogenesis and so could be therapeutically targeted.
- ion channel
- pulmonary artery
- pulmonary hypertension
- Received December 30, 2015.
- Accepted February 12, 2016.