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, and Kwan, Yiu Wa (2013) Acute simvastatin inhibits K-ATP channels of porcine coronary artery myocytes. PLoS ONE, 8 (6). e66404. pp. 1-16.

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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 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 mM)-and pinacidil (10 μM)-mediated opening of whole-cell K-ATP channels of arterial myocytes. Simvastatin (10 mu M) and AICAR (1 mM) elicited a time-dependent, compound C (1 μM)-sensitive [H-3]-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-AMPK alpha-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 K-ATP channels, and phosphorylation of AMPK alpha-Thr¹⁷² and PP2A-Tyr³⁰⁷ resulted. Phosphorylation of PP2A-Tyr³⁰⁷ occurs at a site downstream of AMPKα-Thr¹⁷² phosphorylation.

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