Overexpression of humanKCNA5increasesIK(V)and enhances apoptosis

Elena E. Brevnova, Oleksandr Platoshyn, Shen Zhang, Jason X.-J. Yuan
2004 American Journal of Physiology - Cell Physiology  
Apoptotic cell shrinkage, an early hallmark of apoptosis, is regulated by K ϩ efflux and K ϩ channel activity. Inhibited apoptosis and downregulated K ϩ channels in pulmonary artery smooth muscle cells (PASMC) have been implicated in development of pulmonary vascular medial hypertrophy and pulmonary hypertension. The objective of this study was to test the hypothesis that overexpression of KCNA5, which encodes a delayed-rectifier voltage-gated K ϩ (Kv) channel, increases K ϩ currents and
more » ... s apoptosis. Transient transfection of KCNA5 caused 25-to 34-fold increase in KCNA5 channel protein level and 24-to 29-fold increase in Kv channel current (I K(V)) at ϩ60 mV in COS-7 and rat PASMC, respectively. In KCNA5-transfected COS-7 cells, staurosporine (ST)-mediated increases in caspase-3 activity and the percentage of cells undergoing apoptosis were both enhanced, whereas basal apoptosis (without ST stimulation) was unchanged compared with cells transfected with an empty vector. In rat PASMC, however, transfection of KCNA5 alone caused marked increase in basal apoptosis, in addition to enhancing ST-mediated apoptosis. Furthermore, ST-induced apoptotic cell shrinkage was significantly accelerated in COS-7 cells and rat PASMC transfected with KCNA5, and blockade of KCNA5 channels with 4-aminopyridine (4-AP) reduced K ϩ currents through KCNA5 channels and inhibited ST-induced apoptosis in KCNA5-transfected COS-7 cells. Overexpression of the human KCNA5 gene increases K ϩ currents (i.e., K ϩ efflux or loss), accelerates apoptotic volume decrease (AVD), increases caspase-3 activity, and induces apoptosis. Induction of apoptosis in PASMC by KCNA5 gene transfer may serve as an important strategy for preventing the progression of pulmonary vascular wall thickening and for treating patients with idiopathic pulmonary arterial hypertension (IPAH). potassium ion channel; pulmonary hypertension
doi:10.1152/ajpcell.00050.2004 pmid:15140747 fatcat:oskakqmdvzcdnfacnqnpmwhtzu