title: Burn-induced apoptosis of cardiomyocytes is survivin dependent and regulated by PI3K/Akt, p38 MAPK and ERK pathways.
abstract: Survivin belongs to the family of genes known as inhibitors of apoptosis, and although it has been implicated in the prevention of cancer, its potential role in burn-induced cardiac injury is unknown. In this study, we investigated the effects of survivin blockade on burn-induced cardiac apoptosis. Using a standardized Sprague-Dawley rat model of third-degree burn injury over 40% of total body surface area, apoptosis was measured in vivo followed by in vitro assessment of burn serum-stimulated cardiomyocytes. Based on the Western blot analyses, real-time PCR, ELISA, and TUNEL, apoptosis and caspase activation both in vivo and in vitro were significantly increased after severe burn injury, while survivin expression was increased (up to 2.90-fold) during the early stage of burn injury and was almost completely abolished 8 h after the burn. Survivin-deficient cardiomyocytes, as well as hearts from rats treated with the survivin inhibitor YM155, exhibited increased caspase-3 protein and mRNA expression and apoptosis ratio at different times after the burn. Furthermore, inhibition of ERK, phosphoinositol 3-kinase contributed the burn serum-induced increase in apoptosis and caspase-3 protein expression, and decreased survivin expression, whereas burn serum-induced increase in apoptosis was attenuated by P38 mitogen-activated protein kinase inhibition. These data identify survivin as a critical anti-apoptotic regulator of cardiomyocytes after burn injury. ERK, P38 MAPK and PI3K were found to be upstream regulators of survivin.
authors.affiliation: Institute of Materia Medica, School of Pharmacy, Fourth Military Medical University, 169 West Changle Road, Xi'an 710032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Xie
authors.forename: Xiao-Qiang
authors.initials: XQ
authors.lastname: Li
authors.forename: Xiao-Kai
authors.initials: XK
authors.lastname: Zhang
authors.forename: Yue-Tao
authors.initials: YT
authors.lastname: Chen
authors.forename: Rong
authors.initials: R
authors.lastname: Kang
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Shan
authors.initials: S
authors.lastname: Miao
authors.forename: Si-Wang
authors.initials: SW
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002056:Burns / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D000077022:Survivin; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C516989:Birc5 protein, rat; D016207:Cytokines; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases