Secreted frizzled related protein 4 reduces fibrosis scar size and ameliorates cardiac function after ischemic injury.
Expression of the Wnt modulator secreted frizzled related protein 4 (Sfrp4) is upregulated after heart ischemic injury. We show that intramuscular administration of recombinant Sfrp4 to rat heart ischemic injury and recanalization models prevents further deterioration of cardiac function after the ischemic injury. The effect of Sfrp4 persisted for at least 20 weeks when Sfrp4 was administered in a slow release system (Sfrp4-polyhedra) to both acute and subacute ischemic models. The histology of the dissected heart showed that the cardiac wall was thicker and the area of acellular scarring was smaller in Sfrp4-treated hearts than in controls. Increased amounts of both the inactive serine 9-phosphorylated form of glycogen synthase kinase (GSK)-3β and the active form of β-catenin were observed by immunohistology 3 days after lateral anterior descendant ligation in control, but not in Sfrp4-treated hearts. All together, we show that administration of Sfrp4 interferes with canonical Wnt signaling that could mediate the formation of acellular scar and consequently contributes to the prevention of aggravation of cardiac function.
Foundation for Biomedical Research and Innovation TR1308, Kobe, Japan.
Kentaro
K
Matsushima
Takashi
T
Suyama
Chiemi
C
Takenaka
Naoki
N
Nishishita
Keiko
K
Ikeda
Yoshito
Y
Ikada
Yoshiki
Y
Sawa
Lars Martin
LM
Jakt
Hajime
H
Mori
Shin
S
Kawamata
D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005355:Fibrosis; D006334:Heart Function Tests; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D011518:Proto-Oncogene Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
D001672:Biocompatible Materials; D002316:Cardiotonic Agents; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C118723:SFRP4 protein, human; D000094742:Secreted Frizzled-Related Proteins; C498454:Sfrp4 protein, mouse