Nitric oxide induces apoptosis by activating K+channels in pulmonary vascular smooth muscle cells

Nitric oxide (NO) is an endogenous endothelium-derived relaxing factor that regulates vascular smooth muscle cell proliferation and apoptosis. This study investigated underlying mechanisms involved in NO-induced apoptosis in human and rat pulmonary artery smooth muscle cells (PASMC). Exposure of PASMC to NO, which was derived from the NO donor S-nitroso- N-acetyl-penicillamine, increased the percentage of cells undergoing apoptosis. Increasing extracellular K+concentration to 40 mM or blocking K+channels with 1 mM tetraethylammonia (TEA), 100 nM iberiotoxin (IBTX), and 5 mM 4-aminopyridine (4-AP) significantly inhibited the NO-induced apoptosis. In single PASMC, NO reversibly increased K+currents through the large-conductance Ca2+-activated K+(KCa) channels, whereas TEA and IBTX markedly decreased the KCacurrents. In the presence of TEA, NO also increased K+currents through voltage-gated K+(Kv) channels, whereas 4-AP significantly decreased the Kvcurrents. Opening of KCachannels with 0.3 mM dehydroepiandrosterone increased KCacurrents, induced apoptosis, and further enhanced the NO-mediated apoptosis. Furthermore, NO depolarized the mitochondrial membrane potential. These observations indicate that NO induces PASMC apoptosis by activating KCaand Kvchannels in the plasma membrane. The resulting increase in K+efflux leads to cytosolic K+loss and eventual apoptosis volume decrease and apoptosis. NO-induced apoptosis may also be related to mitochondrial membrane depolarization in PASMC.