Role of 5-HT 2B receptors in cardiomyocyte apoptosis in noradrenaline-induced cardiomyopathy in rats.
1. Serotonin (5-hydroxytryptamine; 5-HT) plays important roles in the development of cardiac hypertrophy via activation of 5-HT receptors. The aim of the present study was to investigate the role of 5-HT(2B) receptors in the development of cardiomyocyte apoptosis and hypertrophy associated with noradrenaline (NA) overload. 2. Cardiac hypertrophy was induced in rats by intraperitoneal injection of 1.5 mg/kg NA for 4 weeks. Starting from Day 15, 5-HT2B receptor antagonist SB 204741 (i.p., 0.5 or 2 mg/kg) or SDZ SER 082 (i.p., 1 mg/kg) was injected twice daily for another 14 days. Whole-cell patch-clamp techniques were used to record ionic currents in freshly isolated ventricular cardiomyocytes. Western blot and terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) assays were used to assess myocardial apoptosis. 3. Expression of 5-HT(2B) receptors was enhanced in the hypertrophic left ventricle induced by NE overload in vivo. The 5-HT(2B) receptor antagonist SB 204741 partially reversed cardiac hypertrophy induced by NE overload (P < 0.05) and decreased L-type calcium currents in ventricular cardiomyocytes (P < 0.05). In addition, SB 204741 notably attenuated myocardial apoptosis, as evidenced by downregulation of Bax and caspase 3 (P < 0.05) and upregulation of the anti-apoptotic Bcl-2 protein (P < 0.05). 4. In conclusion, the data suggest an involvement of 5-HT(2B) receptors in the generation of apoptotic events associated with cardiac remodelling during increased adrenergic stimulation.
Bai
Chong-Feng
CF
Department of Cardiac Surgery, Xijing Hospital, Xi'an, China.
Liu
Jin-Cheng
JC
Zhao
Rong
R
Cao
Wei
W
Liu
Shui-Bin
SB
Zhang
Xiao-Nan
XN
Guo
Hong-Ju
HJ
Yang
Qi
Q
Yi
Ding-Hua
DH
Zhao
Ming-Gao
MG
D000818:Animals; D017209:Apoptosis; D020746:Calcium Channels, L-Type / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D009202:Cardiomyopathies / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000032:analysis; D015536:Down-Regulation; D007211:Indoles / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology*; D009287:Naphthyridines / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044403:Receptor, Serotonin, 5-HT2B / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology*; D058830:Serotonin 5-HT2 Receptor Antagonists; D015854:Up-Regulation; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000032:analysis
C544865:4,5,7a,8,9,10,11,11a-octohydro-7H-10-methylindolol(1,7bc)(2,6)-napthyridine; D020746:Calcium Channels, L-Type; D007211:Indoles; C092756:N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl)urea; D009287:Naphthyridines; D019253:Proto-Oncogene Proteins c-bcl-2; D044403:Receptor, Serotonin, 5-HT2B; D058830:Serotonin 5-HT2 Receptor Antagonists; D051028:bcl-2-Associated X Protein; D012701:Serotonin; D014508:Urea; D053148:Caspase 3; D009638:Norepinephrine