Activation of K+ channels induces apoptosis in vascular smooth muscle cells

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California School of Medicine, San Diego, California 92103-8382 Intracellular K + plays an important role in controlling the cytoplasmic ion homeostasis for maintaining cell volume and inhibiting apoptotic enzymes in the cytosol and nucleus. Cytoplasmic K + concentration is mainly regulated by K + uptake via Na + -K + -ATPase and K + efflux through K + channels in the plasma membrane. Carbonyl cyanide p -trifluoromethoxyphenylhydrazone (FCCP), a protonophore that dissipates the H + gradient across the inner membrane of mitochondria, induces apoptosis in many cell types. In rat and human pulmonary artery smooth muscle cells (PASMC), FCCP opened the large-conductance, voltage- and Ca 2+ -sensitive K + (maxi-K) channels, increased K + currents through maxi-K channels [ I K(Ca) ], and induced apoptosis. Tetraethylammonia (1 mM) and iberiotoxin (100 nM) decreased I K(Ca) by blocking the sarcolemmal maxi-K channels and inhibited the FCCP-induced apoptosis in PASMC cultured in media containing serum and growth factors. Furthermore, inhibition of K + efflux by raising extracellular K + concentration from 5 to 40 mM also attenuated PASMC apoptosis induced by FCCP and the K + ionophore valinomycin. These results suggest that FCCP-mediated apoptosis in PASMC is partially due to an increase of maxi-K channel activity. The resultant K + loss through opened maxi-K channels may serve as a trigger for cell shrinkage and caspase activation, which are major characteristics of apoptosis in pulmonary vascular smooth muscle cells. mitochondrial membrane potential; cytoplasmic calcium; pulmonary artery smooth muscle cells