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.
Mesh Terms:
Animals, Animals, Newborn, Apoptosis, Cardiomyopathies, Cardiotoxicity, Cells, Cultured, Chromatin Immunoprecipitation, Doxorubicin, Heart, Heart Failure, Inflammation, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myocardium, Myocytes, Cardiac, Oligonucleotide Array Sequence Analysis, Oxidative Stress, Protein Domains, RNA, Small Interfering, Rats, Rats, Sprague-Dawley, Signal Transduction, Ubiquitin-Protein Ligases
Sci Rep
Date: Dec. 21, 2015
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