Article: Modulation by simvastatin of iberiotoxin-sensitive, Ca 2+- activated K + channels of porcine coronary artery smooth muscle cells

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Publisher Website: 10.1038/sj.bjp.0707327
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PMID: 17558433

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Title	Modulation by simvastatin of iberiotoxin-sensitive, Ca 2+- activated K + channels of porcine coronary artery smooth muscle cells
Authors	Seto, SW5 Au, ALS5 Lam, TY5 Chim, SSC5 Lee, SMY3 Wan, S5 Tjiu, DCS2 4 Shigemura, N5 Yim, APC5 Chan, SW4 Tsui, SKW5 Leung, GPH1 Kwan, YW5
Issue Date	2007
Publisher	John Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0007-1188&site=1
Citation	British Journal Of Pharmacology, 2007, v. 151 n. 7, p. 987-997 [How to Cite?] DOI: http://dx.doi.org/10.1038/sj.bjp.0707327
Abstract	Background and Purpose: Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase inhibitors) have been demonstrated to reduce cardiovascular mortality. It is unclear how the expression level of HMG CoA reductase in cardiovascular tissues compares with that in cells derived from the liver. We hypothesized that this enzyme exists in different cardiovascular tissues, and simvastatin modulates the vascular iberiotoxin-sensitive Ca 2+- activated K + (BK Ca) channels. Experimental Approaches: Expression of HMG CoA reductase in different cardiovascular preparations was measured. Effects of simvastatin on BK Ca channel gatings of porcine coronary artery smooth muscle cells were evaluated. Key Results: Western immunoblots revealed the biochemical existence of HMG CoA reductase in human cardiovascular tissues and porcine coronary artery. In porcine coronary artery smooth muscle cells, extracellular simvastatin (1, 3 and 10 μM) (hydrophobic), but not simvastatin Na + (hydrophilic), inhibited the BK Ca channels with a minimal recovery upon washout. Isopimaric acid (10 μM)-mediated enhancement of the BK Ca amplitude was reversed by external simvastatin. Simvastatin Na + (10 μM, applied internally), markedly attenuated isopimaric acid (10 μM)-induced enhancement of the BK Ca amplitude. Reduced glutathione (5 mM; in the pipette solution) abolished simvastatin -elicited inhibition. Mevalonolactone (500 μM) and geranylgeranyl pyrophosphate (20 μM) only prevented simvastatin (1 and 3 μM)-induced responses. simvastatin (10 μM) caused a rottlerin (1 μM)-sensitive (cycloheximide (10 μM)-insensitive) increase of PKC-δ protein expression. Conclusions and Implications: Our results demonstrated the biochemical presence of HMG CoA reductase in different cardiovascular tissues, and that simvastatin inhibited the BK Ca channels of the arterial smooth muscle cells through multiple intracellular pathways. © 2007 Nature Publishing Group All rights reserved.
ISSN	0007-1188 2011 Impact Factor: 4.409 2011 SCImago Journal Rankings: 0.406
DOI	http://dx.doi.org/10.1038/sj.bjp.0707327
References	References in Scopus

DC Field	Value
dc.contributor.author	Seto, SW
dc.contributor.author	Au, ALS
dc.contributor.author	Lam, TY
dc.contributor.author	Chim, SSC
dc.contributor.author	Lee, SMY
dc.contributor.author	Wan, S
dc.contributor.author	Tjiu, DCS
dc.contributor.author	Shigemura, N
dc.contributor.author	Yim, APC
dc.contributor.author	Chan, SW
dc.contributor.author	Tsui, SKW
dc.contributor.author	Leung, GPH
dc.contributor.author	Kwan, YW
dc.date.accessioned	2012-10-30T06:13:34Z
dc.date.available	2012-10-30T06:13:34Z
dc.date.issued	2007
dc.description.abstract	Background and Purpose: Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase inhibitors) have been demonstrated to reduce cardiovascular mortality. It is unclear how the expression level of HMG CoA reductase in cardiovascular tissues compares with that in cells derived from the liver. We hypothesized that this enzyme exists in different cardiovascular tissues, and simvastatin modulates the vascular iberiotoxin-sensitive Ca 2+- activated K + (BK Ca) channels. Experimental Approaches: Expression of HMG CoA reductase in different cardiovascular preparations was measured. Effects of simvastatin on BK Ca channel gatings of porcine coronary artery smooth muscle cells were evaluated. Key Results: Western immunoblots revealed the biochemical existence of HMG CoA reductase in human cardiovascular tissues and porcine coronary artery. In porcine coronary artery smooth muscle cells, extracellular simvastatin (1, 3 and 10 μM) (hydrophobic), but not simvastatin Na + (hydrophilic), inhibited the BK Ca channels with a minimal recovery upon washout. Isopimaric acid (10 μM)-mediated enhancement of the BK Ca amplitude was reversed by external simvastatin. Simvastatin Na + (10 μM, applied internally), markedly attenuated isopimaric acid (10 μM)-induced enhancement of the BK Ca amplitude. Reduced glutathione (5 mM; in the pipette solution) abolished simvastatin -elicited inhibition. Mevalonolactone (500 μM) and geranylgeranyl pyrophosphate (20 μM) only prevented simvastatin (1 and 3 μM)-induced responses. simvastatin (10 μM) caused a rottlerin (1 μM)-sensitive (cycloheximide (10 μM)-insensitive) increase of PKC-δ protein expression. Conclusions and Implications: Our results demonstrated the biochemical presence of HMG CoA reductase in different cardiovascular tissues, and that simvastatin inhibited the BK Ca channels of the arterial smooth muscle cells through multiple intracellular pathways. © 2007 Nature Publishing Group All rights reserved.
dc.description.nature	Link_to_subscribed_fulltext
dc.identifier.citation	British Journal Of Pharmacology, 2007, v. 151 n. 7, p. 987-997 [How to Cite?] DOI: http://dx.doi.org/10.1038/sj.bjp.0707327
dc.identifier.doi	http://dx.doi.org/10.1038/sj.bjp.0707327
dc.identifier.epage	997
dc.identifier.hkuros	157508
dc.identifier.issn	0007-1188 2011 Impact Factor: 4.409 2011 SCImago Journal Rankings: 0.406
dc.identifier.issue	7
dc.identifier.pmid	17558433
dc.identifier.scopus	eid_2-s2.0-34547602966
dc.identifier.spage	987
dc.identifier.uri	http://hdl.handle.net/10722/171357
dc.identifier.volume	151
dc.language	eng
dc.publisher	John Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0007-1188&site=1
dc.publisher.place	United Kingdom
dc.relation.ispartof	British Journal of Pharmacology
dc.relation.references	References in Scopus
dc.subject.mesh	Adult
dc.subject.mesh	Aged
dc.subject.mesh	Animals
dc.subject.mesh	Blotting, Western
dc.subject.mesh	Caveolin 1 - Biosynthesis
dc.subject.mesh	Cell Line
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Coronary Vessels - Cytology - Drug Effects - Physiology
dc.subject.mesh	Dose-Response Relationship, Drug
dc.subject.mesh	Enzyme Activation - Drug Effects
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	Hydroxymethylglutaryl-Coa Reductase Inhibitors - Pharmacology
dc.subject.mesh	Imidazoles - Pharmacology
dc.subject.mesh	Male
dc.subject.mesh	Membrane Potentials - Drug Effects
dc.subject.mesh	Middle Aged
dc.subject.mesh	Muscle, Smooth, Vascular - Cytology - Drug Effects - Physiology
dc.subject.mesh	Myocytes, Smooth Muscle - Drug Effects - Metabolism - Physiology
dc.subject.mesh	Peptides - Pharmacology
dc.subject.mesh	Phorbol Esters - Pharmacology
dc.subject.mesh	Potassium Channels, Calcium-Activated - Antagonists & Inhibitors - Metabolism - Physiology
dc.subject.mesh	Protein Kinase C-Delta - Metabolism
dc.subject.mesh	Pyridines - Pharmacology
dc.subject.mesh	Simvastatin - Chemistry - Pharmacology
dc.subject.mesh	Swine
dc.title	Modulation by simvastatin of iberiotoxin-sensitive, Ca 2+- activated K + channels of porcine coronary artery smooth muscle cells
dc.type	Article

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Author Affiliations

The University of Hong Kong
Union Hospital
University of Macau
Hong Kong Polytechnic University
Chinese University of Hong Kong

Article: Modulation by simvastatin of iberiotoxin-sensitive, Ca 2+- activated K + channels of porcine coronary artery smooth muscle cells

The HKU Scholars Hub has contact details for these author(s).