title: Smad1 protects cardiomyocytes from ischemia-reperfusion injury.
abstract: BACKGROUND
  We previously reported that bone morphogenetic protein 2 (BMP2) protected against apoptosis of serum-deprived cardiomyocytes via induction of Bcl-xL through the Smad1 pathway. To investigate whether Smad1 signaling promotes cell survival in the adult heart, we subjected transgenic mice with cardiac-specific overexpression of smad1 gene (Smad1TG) to ischemia-reperfusion (I/R) injury.
  
  
  RESULTS
  The effects of BMP2 or adenovirus-mediated transfection of smad1 on cardiomyocyte survival in hypoxia-reoxygenation were examined using rat neonatal cardiomyocytes. BMP2 and Smad1 each significantly promoted survival and diminished apoptotic death of cardiomyocytes during hypoxia-reoxygenation. Interestingly, Smad1 was found to be activated during I/R in normal mouse heart. To examine physiological and pathological roles of Smad1 in I/R, we generated Smad1TG using the alpha-myosin heavy chain gene promoter. Phosphorylation of Smad1 was found in all smad1 transgene-positive mouse hearts. To examine whether Smad1 prevents injury of cardiomyocytes in vivo, we subjected Smad1TG and age-matched wild-type mice (WT) to I/R injury induced by 1 hour of ligation of the left coronary artery and 1 hour of reperfusion. TUNEL and DNA ladder analyses showed that Smad1TG had significantly smaller myocardial infarctions and fewer apoptotic deaths of cardiomyocytes than did WT. Interestingly, increased expression of Bcl-xL and beta-catenin was more remarkable whereas caspase3 was less activated in Smad1TG heart than in that of WT.
  
  
  CONCLUSIONS
  These findings suggest that the Smad1 signaling pathway plays a role in cardioprotection against I/R injury.
authors.affiliation: Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Masaki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Izumi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oshima
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nakaoka
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kuroda
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Kimura
authors.forename: Shoko
authors.initials: S
authors.lastname: Sugiyama
authors.forename: Kazuo
authors.initials: K
authors.lastname: Terai
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamauchi-Takihara
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawase
authors.forename: Hisao
authors.initials: H
authors.lastname: Hirota
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D015398:Signal Transduction; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection
chemical_list: D051898:Smad1 Protein; C497401:Smad1 protein, mouse