Acute simvastatin inhibits K ATP channels of porcine coronary artery myocytes

• Published in: PloS one 2013, Vol.8 (6), p.e66404-e66404
• Main Authors: Seto, Sai Wang, Au, Alice Lai Shan, Poon, Christina Chui Wa, Zhang, Qian, Li, Rachel Wai Sum, Yeung, John Hok Keung, Kong, Siu Kai, Ngai, Sai Ming, Wan, Song, Ho, Ho Pui, Lee, Simon Ming Yuen, Hoi, Maggie Pui Man, Chan, Shun Wan, Leung, George Pak Heng, Kwan, Yiu Wa
• Format: Article
• Language: English
• Subjects: Adenylate Kinase - metabolism; Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; Animals; Cells, Cultured; Coronary Vessels - cytology; Coronary Vessels - drug effects; Coronary Vessels - metabolism; Cytochrome P-450 Enzyme System - metabolism; Glucose - metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Ion Channel Gating - drug effects; KATP Channels - antagonists & inhibitors; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Patch-Clamp Techniques; Phosphorylation; Protein Phosphatase 2 - metabolism; Ribonucleotides - pharmacology; Simvastatin - pharmacology; Swine
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0066404

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. 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 [Ca(2+)]i, [ATP]i and [glucose]o uptake measurements. 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 [(3)H]-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-Thr(172) and p-PP2A-Tyr(307) expression was observed. The enhanced p-AMPKα-Thr(172) expression was inhibited by compound C, ryanodine (100 µM) and KN93 (10 µM). Simvastatin-induced p-PP2A-Tyr(307) 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. Simvastatin causes ryanodine-sensitive Ca(2+) release which is important for AMPKα-Thr(172) phosphorylation via Ca(2+)/CaMK II. AMPKα-Thr(172) phosphorylation causes [glucose]o uptake (and an [ATP]i increase), closure of KATP channels, and phosphorylation of AMPKα-Thr(172) and PP2A-Tyr(307) resulted. Phosphorylation of PP2A-Tyr(307) occurs at a site downstream of AMPKα-Thr(172) phosphorylation.