Effect of pravastatin on ventricular arrhythmias in infarcted rats: role of connexin43.
Epidemiologic studies showed that men treated with statins appear to have a lower incidence of sudden death than men without statins. However, the specific factor for this remained disappointingly elusive. We assessed whether pravastatin enhanced connexin43 expression after myocardial infarction through attenuation of endothelin-1. Twenty-four hours after ligation of the anterior descending artery, male Wistar rats were randomized to vehicle, pravastatin, mevalonate, bosentan, or a combination of pravastatin and mevalonate or pravastatin and bosentan for 4 wk. Myocardial endothelin-1 levels were significantly elevated in vehicle-treated rats at the border zone compared with sham-operated rats. Myocardial connexin43 expression at the border zone was significantly decreased in vehicle-treated infarcted rats compared with sham-operated rats. Attenuated connexin43 expression was blunted after administration of pravastatin, as assessed by immunofluorescence analysis, Western blotting, and real-time quantitative RT-PCR of connexin43. Bosentan enhanced connexin43 amount in infarcted rats and did not have additional beneficial effects on pravastatin-treated rats. Arrhythmic scores during programmed stimulation in vehicle-treated rats were significantly higher than scores in those treated with pravastatin. In contrast, the beneficial effects of pravastatin-induced connexin43 were abolished by the addition of mevalonate and a protein kinase C inducer. In addition, the amount of connexin43 showed significant increase after addition of bisindolylmaleimide, implicating that protein kinase C is a relevant target in endothelin-1-mediated connexin43 expression. Thus chronic use of pravastatin after infarction, resulting in enhanced connexin43 amount by attenuation of mevalonate-dependent endothelin-1 through a protein kinase C-dependent pathway, may attenuate the arrhythmogenic response to programmed electrical stimulation.
Chen
Chien-Chang
CC
Department of Cosmetic Science, Chia Nan University of Pharmacy Science, Tainan, Taiwan.
Lien
Hsiao-Yin
HY
Hsu
Yu-Jung
YJ
Lin
Chih-Chan
CC
Shih
Chun-Ming
CM
Lee
Tsung-Ming
TM
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D015153:Blotting, Western; D000077300:Bosentan; D002304:Cardiac Pacing, Artificial; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D009203:Myocardial Infarction / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D017035:Pravastatin / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D014463:Ultrasonography
D000889:Anti-Arrhythmia Agents; D018031:Connexin 43; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D013449:Sulfonamides; D011493:Protein Kinase C; D017035:Pravastatin; C088060:bisindolylmaleimide; D000077300:Bosentan; D008798:Mevalonic Acid