Smad1 protects cardiomyocytes from ischemia-reperfusion injury.
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.
Masaki
Mitsuru
M
Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita City, Osaka 565-0871, Japan.
Izumi
Masahiro
M
Oshima
Yuichi
Y
Nakaoka
Yoshikazu
Y
Kuroda
Tadashi
T
Kimura
Ryusuke
R
Sugiyama
Shoko
S
Terai
Kazuo
K
Kitakaze
Masafumi
M
Yamauchi-Takihara
Keiko
K
Kawase
Ichiro
I
Hirota
Hisao
H
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
D051898:Smad1 Protein; C497401:Smad1 protein, mouse