The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia.
PLoS One. 2013 Jun 17;8(6):e66404. doi: 10.1371/journal.pone.0066404. Print 2013.
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.
他汀类药物（3-羟基-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶抑制剂）的使用对心血管系统有有益的影响。然而，他汀类药物对血管 KATP 通道门控的影响尚不清楚。
分离并去除猪左前降支冠状动脉和人左内乳动脉的内皮，用于张力测量和 Western 免疫印迹。酶解/培养的动脉肌细胞用于膜片钳电生理研究以及[Ca(2+)]i、[ATP]i 和[glucose]o摄取测量。
克罗马林（10 nM 至 10 μM）和匹那地尔（10 nM 至 10 μM）诱导的猪冠状动脉浓度依赖性松弛被辛伐他汀（3 和 10 μM）抑制。辛伐他汀（1、3 和 10 μM）以 okadaic acid（10 nM）敏感的方式抑制克罗马林（10 μM）和匹那地尔（10 μM）介导的动脉肌细胞全细胞 KATP 通道开放。辛伐他汀（10 μM）和 AICAR（1 mM）引起时间依赖性、化合物 C（1 μM）敏感的[(3)H]-2-脱氧葡萄糖摄取和[ATP]i 水平增加。观察到辛伐他汀在时间（2-30 分钟）和浓度（0.1-10 μM）依赖性上增加 p-AMPKα-Thr(172)和 p-PP2A-Tyr(307)的表达。增强的 p-AMPKα-Thr(172)表达被化合物 C、ryanodine（100 μM）和 KN93（10 μM）抑制。辛伐他汀诱导的 p-PP2A-Tyr(307)表达被 okadaic acid、化合物 C、ryanodine、KN93、phloridzin（1 mM）、ouabain（10 μM）和[glucose]o 缺乏或[Na(+)]o 缺乏条件抑制。
辛伐他汀引起ryanodine 敏感的 Ca(2+)释放，这对于通过 Ca(2+)/CaMK II 进行 AMPKα-Thr(172)磷酸化很重要。AMPKα-Thr(172)磷酸化导致[glucose]o 摄取（和[ATP]i 增加）、KATP 通道关闭以及 AMPKα-Thr(172)和 PP2A-Tyr(307)的磷酸化。PP2A-Tyr(307)的磷酸化发生在 AMPKα-Thr(172)磷酸化的下游位点。
