17beta-Estradiol decreases vulnerability to ventricular arrhythmias by preserving connexin43 protein in infarcted rats.
Epidemiological studies showed that a lower mortality rate of sudden cardiac death among women than among men may depend on the action of female sex hormones. This study assessed whether 17beta-estradiol exerts anti-arrhythmic effects through enhanced Connexin43 (Cx43) expression after infarction. Two weeks after ovariectomy, female Wistar rats were randomly assigned to coronary artery ligation or sham-operation. Twenty-four hours after coronary ligation, ovariectomized rats were randomized into vehicle, subcutaneous estradiol treatment, tamoxifen, or subcutaneous estradiol treatment+tamoxifen and followed for 4weeks. To verify the role of estradiol-related nitric oxide in modulating the expression of Cx43, N-nitro-L-arginine methyl ester was also assessed in an in vitro study. Myocardial Cx43 expression revealed a significant decrease in vehicle-treated infarcted rats compared with sham-operated rats at 24h and 4weeks after infarction. Attenuated Cx43 expression was blunted after administering estradiol, assessed by immunofluorescent analysis, Western blotting, and real-time quantitative RT-PCR of Cx43. The vulnerability for ventricular arrhythmia during programmed stimulation in estradiol-treated infarcted rats was significantly lower than in vehicle-treated infarcted rats. The beneficial effect of estradiol on Cx43 was abolished by tamoxifen. In addition, the invitro study demonstrated that the amount of Cx43 showed significant reduction after adding N-nitro-L-arginine methyl ester. Chronic administration of estradiol after infarction is associated with attenuated reduction of gap junction proteins probably through a nitric oxide-dependent pathway via the estrogen receptor and thus plays a critical role in the beneficial effect on arrhythmic vulnerability response to programmed electrical stimulation.
Chen
Chien-Chang
CC
Cardiology Section, Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan.
Lin
Chih-Chan
CC
Lee
Tsung-Ming
TM
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D001835:Body Weight / Q000187:drug effects; D018031:Connexin 43 / Q000378:metabolism*; D004452:Echocardiography; D055724:Electrophysiological Phenomena / Q000187:drug effects; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D004967:Estrogens / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014599:Uterus / Q000187:drug effects / Q000473:pathology
D018031:Connexin 43; D004967:Estrogens; D009569:Nitric Oxide; D004958:Estradiol; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester