title: Cardiomyocyte-specific overexpression of human stem cell factor protects against myocardial ischemia and reperfusion injury.
abstract: BACKGROUND
  Cardiomyocyte-specific overexpression of human membrane-associated stem cell factor (hSCF) improves cardiac function post-myocardial infarction. However, whether hSCF overexpression protects the heart from ischemia and reperfusion (I/R) injury is unknown. We aimed to investigate the effects of cardiomyocyte-specific overexpression of hSCF on cardiac injury after acute myocardial I/R and related cellular and molecular signaling mechanisms.
  
  
  RESULTS
  Wild-type (WT) and hSCF/tetracycline transactivator (tTA) transgenic mice (hSCF/tTA) were subjected to myocardial ischemia for 45 min followed by 3 h of reperfusion. Infarct size and myocardial apoptosis were decreased in hSCF/tTA compared to WT mice (P<0.05). Furthermore, these cardioprotective effects in the hSCF/tTA mice were abrogated by doxycycline, which turned off hSCF overexpression, and by a PI3 kinase inhibitor LY294002. Myocardial expression of insulin-like growth factor (IGF)-1 and hepatocyte growth factor (HGF), which are upstream activators of Akt signaling, was significantly increased in hSCF/tTA compared to WT mice after I/R (P<0.05), and was associated with higher number of c-kit(+) cardiac stem cells (CSCs) (P<0.05). Inhibition of c-kit signaling by ACK2 treatment abolished these protective effects in hSCF/tTA mice.
  
  
  CONCLUSIONS
  Cardiomyocyte-specific overexpression of hSCF protects the heart from I/R injury. The cardioprotective effects of hSCF overexpression are mediated by increased c-kit(+) CSCs, enhanced growth factor expression and activation of Akt signaling pathway.
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Fu-Li
authors.initials: FL
authors.lastname: Xiang
authors.forename: Xiangru
authors.initials: X
authors.lastname: Lu
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.forename: Qingping
authors.initials: Q
authors.lastname: Feng
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D019089:Stem Cell Factor / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: D002316:Cardiotonic Agents; D019089:Stem Cell Factor
keywords: Akt; Ischemia/reperfusion injury; Stem cell factor