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 Ca(2+)-activated K+ (K(Ca)) channels, whereas TEA and IBTX markedly decreased the K(Ca) currents. In the presence of TEA, NO also increased K+ currents through voltage-gated K+ (K(v)) channels, whereas 4-AP significantly decreased the K(v) currents. Opening of K(Ca) channels with 0.3 mM dehydroepiandrosterone increased K(Ca) currents, 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 K(Ca) and K(v) channels 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.
Krick
Stefanie
S
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California School of Medicine, 200 W. Arbor Dr., San Diego, CA 92103-8382, USA.
Platoshyn
Oleksandr
O
Sweeney
Michele
M
McDaniel
Sharon S
SS
Zhang
Shen
S
Rubin
Lewis J
LJ
Yuan
Jason X-J
JX
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D004533:Egtazic Acid / Q000494:pharmacology; D005456:Fluorescent Dyes; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011651:Pulmonary Artery / Q000166:cytology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology*; D012604:Scorpion Venoms / Q000494:pharmacology; D019789:Tetraethylammonium / Q000494:pharmacology
D005456:Fluorescent Dyes; D020030:Nitric Oxide Donors; D010455:Peptides; D015221:Potassium Channels; D012604:Scorpion Venoms; D020112:Rhodamine 123; D009569:Nitric Oxide; D004533:Egtazic Acid; D019789:Tetraethylammonium; C064719:iberiotoxin; D026423:S-Nitroso-N-Acetylpenicillamine