Augmented K(+) currents and mitochondrial membrane depolarization in pulmonary artery myocyte apoptosis.
The balance between apoptosis and proliferation in pulmonary artery smooth muscle cells (PASMCs) is important in maintaining normal pulmonary vascular structure. Activity of voltage-gated K(+) (K(V)) channels has been demonstrated to regulate cell apoptosis and proliferation. Treatment of PASMCs with staurosporine (ST) induced apoptosis in PASMCs, augmented K(V) current [I(K(V))], and induced mitochondrial membrane depolarization. High K(+) (40 mM) negligibly affected the ST-induced mitochondrial membrane depolarization but inhibited the ST-induced I(K(V)) increase and apoptosis. Blockade of K(V) channels with 4-aminopyridine diminished I(K(V)) and markedly decreased the ST-mediated apoptosis. Furthermore, the ST-induced apoptosis was preceded by the increase in I(K(V)). These results indicate that ST induces PASMC apoptosis by activation of plasmalemmal K(V) channels and mitochondrial membrane depolarization. The increased I(K(V)) would result in an apoptotic volume decrease due to a loss of cytosolic K(+) and induce apoptosis. The mitochondrial membrane depolarization would cause cytochrome c release, activate the cytosolic caspases, and induce apoptosis. Inhibition of K(V) channels would thus attenuate PASMC apoptosis.
Krick
S
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Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California School of Medicine, San Diego, California 92103, USA.
Platoshyn
O
O
McDaniel
S S
SS
Rubin
L J
LJ
Yuan
J X
JX
D015761:4-Aminopyridine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000493:pharmacokinetics*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D011651:Pulmonary Artery / Q000166:cytology*; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D019311:Staurosporine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D020112:Rhodamine 123; D015761:4-Aminopyridine; D019311:Staurosporine; D011188:Potassium