title: Endostatin is protective against monocrotaline-induced right heart disease through the inhibition of T-type Ca(2+) channel.
abstract: Endostatin (ES), a C-terminal fragment of collagen XVIIIα1, has a potent anti-angiogenic effect. ES prevents tumor proliferation through inhibiting T-type Ca(2+) channel. T-type Ca(2+) channel is re-expressed during heart diseases including monocrotaline (MCT)-induced right heart failure. The present study aimed to clarify the effects of ES on T-type Ca(2+) channel and pathogenesis of MCT-induced right ventricular disease. MCT or saline was injected intraperitoneally to rats. After cardiomyocytes were isolated from right ventricles (RVs), T-type Ca(2+) channel current (I CaT) was measured by a patch-clamp method. After ES small interfering RNA (siRNA) or control siRNA (20 μg) was administrated for 1 week via the right jugular vein 1 week after MCT injection, echocardiography and histological analysis were done. I CaT was significantly increased in RV from MCT-injected rats, and ES significantly inhibited it. The survival rate of ES siRNA-administrated MCT rats (MCT ES si group) was decreased. In echocardiography, although ES siRNA did not affect pulmonary arterial pressure, RV systolic function was impaired in MCT ES si group compared with control siRNA-administrated MCT rats (MCT cont si group). In the histological analysis of RV, ES expression was increased in MCT cont si group, and ES siRNA inhibited it. Furthermore, although MCT cont si group showed only cardiomyocyte hypertrophy, MCT ES si group showed notable enlargement of intercellular spaces. The present study for the first time revealed that ES inhibits T-type Ca(2+) channel activity in RV from MCT-injected rats. ES gene knockdown deteriorates MCT-induced right heart disease. ES is thus cardioprotective possibly through inhibiting T-type Ca(2+) channel activity.
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 bancho 35-1, Towada, Aomori, 034-8628, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Imoto
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 bancho 35-1, Towada, Aomori, 034-8628, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kumatani
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 bancho 35-1, Towada, Aomori, 034-8628, Japan. mokada@vmas.kitasato-u.ac.jp.
authors.forename: Muneyoshi
authors.initials: M
authors.lastname: Okada
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 bancho 35-1, Towada, Aomori, 034-8628, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamawaki
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002460:Cell Line; D004452:Echocardiography / Q000379:methods; D043169:Endostatins / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism*; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D016686:Monocrotaline / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013599:Systole / Q000187:drug effects / Q000502:physiology
chemical_list: D020747:Calcium Channels, T-Type; D043169:Endostatins; D016686:Monocrotaline
keywords: Cardiomyocyte; Endostatin; Right heart failure; T-type Ca2+ channel