Protection against doxorubicin-induced myocardial dysfunction in mice by cardiac-specific expression of carboxyl terminus of hsp70-interacting protein.
Carboxyl terminus of Hsp70-interacting protein (CHIP) is a critical ubiquitin ligase/cochaperone to reduce cardiac oxidative stress, inflammation, cardiomyocyte apoptosis and autophage etc. However, it is unclear whether overexpression of CHIP in the heart would exert protective effects against DOX-induced cardiomyopathy. Cardiac-specific CHIP transgenic (CHIP-TG) mice and the wild-type (WT) littermates were treated with DOX or saline. DOX-induced cardiac atrophy, dysfunction, inflammation, oxidative stress and cardiomyocyte apoptosis were significantly attenuated in CHIP-TG mice. CHIP-TG mice also showed higher survival rate than that of WT mice (40% versus 10%) after 10-day administration of DOX. In contrast, knockdown of CHIP by siRNA in vitro further enhanced DOX-induced cardiotoxic effects. Global gene microarray assay revealed that after DOX-treatment, differentially expressed genes between WT and CHIP-TG mice were mainly involved in apoptosis, atrophy, immune/inflammation and oxidative stress. Mechanistically, CHIP directly promotes ubiquitin-mediated degradation of p53 and SHP-1, which results in activation of ERK1/2 and STAT3 pathways thereby ameliorating DOX-induced cardiac toxicity.
Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
Lei
L
Wang
Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
Tian-Peng
TP
Zhang
Department of Pathophysiology, School of Basic Medical Sciences, Baotou Medical College, Baotou 014060, China.
Yuan
Y
Zhang
Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
Hai-Lian
HL
Bi
Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
Xu-Min
XM
Guan
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
Hong-Xia
HX
Wang
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
Xia
X
Wang
Beijing AnZhen Hospital the Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Beijing 100029, China.
Jie
J
Du
Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
Yun-Long
YL
Xia
Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.|Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, Dalian 116044, China.
Hui-Hua
HH
Li
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D009202:Cardiomyopathies / Q000139:chemically induced; D066126:Cardiotoxicity; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004317:Doxorubicin / Q000009:adverse effects*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006333:Heart Failure / Q000503:physiopathology; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D000072417:Protein Domains; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000378:metabolism*
D034741:RNA, Small Interfering; D004317:Doxorubicin; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases