Acute simvastatin inhibits K ATP channels of porcine coronary artery myocytes.
<h4>Background</h4>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.<h4>Methods</h4>Pig left anterior des...
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oai:doaj.org-article:1ea445f0492142abb247dac9421499752021-11-18T07:41:32ZAcute simvastatin inhibits K ATP channels of porcine coronary artery myocytes.1932-620310.1371/journal.pone.0066404https://doaj.org/article/1ea445f0492142abb247dac9421499752013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23799098/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.Sai Wang SetoAlice Lai Shan AuChristina Chui Wa PoonQian ZhangRachel Wai Sum LiJohn Hok Keung YeungSiu Kai KongSai Ming NgaiSong WanHo Pui HoSimon Ming Yuen LeeMaggie Pui Man HoiShun Wan ChanGeorge Pak Heng LeungYiu Wa KwanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 6, p e66404 (2013) |
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Medicine R Science Q |
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Medicine R Science Q Sai Wang Seto Alice Lai Shan Au Christina Chui Wa Poon Qian Zhang Rachel Wai Sum Li John Hok Keung Yeung Siu Kai Kong Sai Ming Ngai Song Wan Ho Pui Ho Simon Ming Yuen Lee Maggie Pui Man Hoi Shun Wan Chan George Pak Heng Leung Yiu Wa Kwan Acute simvastatin inhibits K ATP channels of porcine coronary artery myocytes. |
| description |
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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. |
| format |
article |
| author |
Sai Wang Seto Alice Lai Shan Au Christina Chui Wa Poon Qian Zhang Rachel Wai Sum Li John Hok Keung Yeung Siu Kai Kong Sai Ming Ngai Song Wan Ho Pui Ho Simon Ming Yuen Lee Maggie Pui Man Hoi Shun Wan Chan George Pak Heng Leung Yiu Wa Kwan |
| author_facet |
Sai Wang Seto Alice Lai Shan Au Christina Chui Wa Poon Qian Zhang Rachel Wai Sum Li John Hok Keung Yeung Siu Kai Kong Sai Ming Ngai Song Wan Ho Pui Ho Simon Ming Yuen Lee Maggie Pui Man Hoi Shun Wan Chan George Pak Heng Leung Yiu Wa Kwan |
| author_sort |
Sai Wang Seto |
| title |
Acute simvastatin inhibits K ATP channels of porcine coronary artery myocytes. |
| title_short |
Acute simvastatin inhibits K ATP channels of porcine coronary artery myocytes. |
| title_full |
Acute simvastatin inhibits K ATP channels of porcine coronary artery myocytes. |
| title_fullStr |
Acute simvastatin inhibits K ATP channels of porcine coronary artery myocytes. |
| title_full_unstemmed |
Acute simvastatin inhibits K ATP channels of porcine coronary artery myocytes. |
| title_sort |
acute simvastatin inhibits k atp channels of porcine coronary artery myocytes. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/1ea445f0492142abb247dac942149975 |
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