Acute Simvastatin Inhibits KATP Channels of Porcine Coronary Artery Myocytes
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AbstractBackground:Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors) consumption provides beneficial effects on cardiovascular systems. However, effects of statins on vascular KATP channel gatings are unknown.Methods:Pig left anterior descending coronary artery and human left internal mammary artery were isolated and endothelium-denuded for tension measurements and Western immunoblots. Enzymatically-dissociated/cultured arterial myocytes were used for patch-clamp electrophysiological studies and for [Ca2+]i, [ATP]i and [glucose]o uptake measurements.Results:The cromakalim (10 nM to 10 μM)- and pinacidil (10 nM to 10 μM)-induced concentration-dependent relaxation of porcine coronary artery was inhibited by simvastatin (3 and 10 μM). Simvastatin (1, 3 and 10 μM) suppressed (in okadaic acid (10 nM)-sensitive manner) cromakalim (10 μM)- and pinacidil (10 μM)-mediated opening of whole-cell KATP channels of arterial myocytes. Simvastatin (10 μM) and AICAR (1 mM) elicited a time-dependent, compound C (1 μM)-sensitive [3H]-2-deoxy-glucose uptake and an increase in [ATP]i levels. A time (2-30 min)- and concentration (0.1-10 μM)-dependent increase by simvastatin of p-AMPKα-Thr172 and p-PP2A-Tyr307 expression was observed. The enhanced p-AMPKα-Thr172 expression was inhibited by compound C, ryanodine (100 μM) and KN93 (10 μM). Simvastatin-induced p-PP2A-Tyr307 expression was suppressed by okadaic acid, compound C, ryanodine, KN93, phloridzin (1 mM), ouabain (10 μM), and in [glucose]o-free or [Na+]o-free conditions.Conclusions:Simvastatin causes ryanodine-sensitive Ca2+ release which is important for AMPKα-Thr172 phosphorylation via Ca2+/CaMK II. AMPKα-Thr172 phosphorylation causes [glucose]o uptake (and an [ATP]i increase), closure of KATP channels, and phosphorylation of AMPKα-Thr172 and PP2A-Tyr307 resulted. Phosphorylation of PP2A-Tyr307 occurs at a site downstream of AMPKα-Thr172 phosphorylation. © 2013 Seto et al.
All Author(s) ListSeto S.W., Au A.L.S., Poon C.C.W., Zhang Q., Li R.W.S., Yeung J.H.K., Kong S.K., Ngai S.M., Wan S., Ho H.P., Lee S.M.Y., Hoi M.P.M., Chan S.W., Leung G.P.H., Kwan Y.W.
Journal namePLoS ONE
Volume Number8
Issue Number6
PublisherPublic Library of Science
Place of PublicationUnited States
LanguagesEnglish-United Kingdom

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