Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/5857
Title: Acute simvastatin inhibits K[sub ATP] channels of porcine coronary artery myocytes
Authors: Seto, SW
Au, ALS
Poon, CCW
Zhang, Q
Li, RWS
Yeung, JHK
Kong, SK
Ngai, SM
Wan, S
Ho, HP
Lee, SMY
Hoi, MPM
Chan, SW
Leung, GPH
Kwan, YW
Issue Date: 17-Jun-2013
Publisher: Public Library of Science
Source: PLoS one, 17 June 2013, v. 8, no. 6, e66404, p. 1-16 How to cite?
Journal: PLoS one 
Abstract: Background: 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 K[sub ATP] 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⁺][sub i], [ATP][sub i] and [glucose][sub 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][sub 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][sub o]-free or [Na⁺][sub 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.
URI: http://hdl.handle.net/10397/5857
EISSN: 1932-6203
DOI: 10.1371/journal.pone.0066404
Rights: © 2013 Seto et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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