title: Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats.
abstract: BACKGROUND
  Excessive myocardial fibrosis impairs cardiac function in hypertensive hearts. Roles of transforming growth factor (TGF)-beta in myocardial remodeling and cardiac dysfunction were examined in pressure-overloaded rats.
  
  
  RESULTS
  Pressure overload was induced by a suprarenal aortic constriction in Wistar rats. Fibroblast activation (proliferation and phenotype transition to myofibroblasts) was observed after day 3 and peaked at days 3 to 7. Thereafter, myocyte hypertrophy and myocardial fibrosis developed by day 28. At day 28, echocardiography showed normal left ventricular fractional shortening, but the decreased ratio of early to late filling velocity of the transmitral Doppler velocity and hemodynamic measurement revealed left ventricular end-diastolic pressure elevation, indicating normal systolic but abnormal diastolic function. Myocardial TGF-beta mRNA expression was induced after day 3, peaked at day 7, and remained modestly increased at day 28. An anti-TGF-beta neutralizing antibody, which was administered intraperitoneally daily from 1 day before operation, inhibited fibroblast activation and subsequently prevented collagen mRNA induction and myocardial fibrosis, but not myocyte hypertrophy. Neutralizing antibody reversed diastolic dysfunction without affecting blood pressure and systolic function.
  
  
  CONCLUSIONS
  TGF-beta plays a causal role in myocardial fibrosis and diastolic dysfunction through fibroblast activation in pressure-overloaded hearts. Our findings may provide an insight into a new therapeutic strategy to prevent myocardial fibrosis and diastolic dysfunction in pressure-overloaded hearts.
authors.affiliation: Cardiovascular Research Institute and Internal Medicine III, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kuwahara
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kai
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tokuda
authors.forename: Mamiko
authors.initials: M
authors.lastname: Kai
authors.forename: Akira
authors.initials: A
authors.lastname: Takeshita
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Imaizumi
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D003971:Diastole; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D006439:Hemodynamics; D006973:Hypertension / Q000473:pathology / Q000503:physiopathology; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D011312:Pressure; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D000906:Antibodies; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta