title: Postinfarction gene therapy against transforming growth factor-beta signal modulates infarct tissue dynamics and attenuates left ventricular remodeling and heart failure.
abstract: BACKGROUND
  Fibrosis and progressive failure are prominent pathophysiological features of hearts after myocardial infarction (MI). We examined the effects of inhibiting transforming growth factor-beta (TGF-beta) signaling on post-MI cardiac fibrosis and ventricular remodeling and function.
  
  
  RESULTS
  MI was induced in mice by left coronary artery ligation. An adenovirus harboring soluble TGF-beta type II receptor (Ad.CAG-sTbetaRII), a competitive inhibitor of TGF-beta, was then injected into the hindlimb muscles on day 3 after MI (control, Ad.CAG-LacZ). Post-MI survival was significantly improved among sTbetaRII-treated mice (96% versus control at 71%), which also showed a significant attenuation of ventricular dilatation and improved function 4 weeks after MI. At the same time, histological analysis showed reduced fibrous tissue formation. Although MI size did not differ in the 2 groups, MI thickness was greater and circumference was smaller in the sTbetaRII-treated group; within the infarcted area, alpha-smooth muscle actin-positive cells were abundant, which might have contributed to infarct contraction. Apoptosis among myofibroblasts in granulation tissue during the subacute stage (10 days after MI) was less frequent in the sTbetaRII-treated group, and sTbetaRII directly inhibited Fas-induced apoptosis in cultured myofibroblasts. Finally, treatment of MI-bearing mice with sTbetaRII was ineffective if started during the chronic stage (4 weeks after MI).
  
  
  CONCLUSIONS
  Postinfarction gene therapy aimed at suppressing TGF-beta signaling mitigates cardiac remodeling by affecting cardiac fibrosis and infarct tissue dynamics (apoptosis inhibition and infarct contraction). This suggests that such therapy may represent a new approach to the treatment of post-MI heart failure, applicable during the subacute stage.
authors.affiliation: Second Department of Internal Medicine, Gifu University School of Medicine, Japan.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Okada
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Kosai
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Li
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Masayasu
authors.initials: M
authors.lastname: Esaki
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yuge
authors.forename: Shusaku
authors.initials: S
authors.lastname: Miyata
authors.forename: Rumi
authors.initials: R
authors.lastname: Maruyama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mikami
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
authors.forename: Takako
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D017209:Apoptosis; D001667:Binding, Competitive; D004195:Disease Models, Animal; D005355:Fibrosis / Q000517:prevention & control / Q000628:therapy; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D006333:Heart Failure / Q000517:prevention & control* / Q000628:therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D010599:Pharmacokinetics; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II