Abstract
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.
Highlights
carboxyl terminus of Hsp70-interacting protein (CHIP) is known to be a dual-function cochaperone/ubiquitin ligase that is highly expressed in the heart and other tissue cells
We provide the first evidence that CHIP in vivo and in vitro protects against DOX-induced cardiac apoptosis, atrophy, inflammatory and oxidative stress resulting in prevention of cardiac dysfunction and improvement of mouse survival
The precise mechanisms whereby DOX induces myocardial injury have not been fully elucidated, it is widely accepted that the DOX induces cardiac injury via several mechanisms, including activation of ubiquitin-proteasome system, sarcomere reorganization, induction of proinflammatory cytokines, free radical generation and apoptotic cell death that are the typical changes in DOX-induced heart failure[23]
Summary
CHIP is known to be a dual-function cochaperone/ubiquitin ligase that is highly expressed in the heart and other tissue cells. On the basis of previous findings, we postulated that increased CHIP levels would ameliorate DOX-induced cardiotoxicity. To test this hypothesis, wild-type (WT) and CHIP transgenic mice (CHIP-TG) were administered with a single dose of DOX (20 mg/kg; i.p.) for 5 or 10 days. We showed that cardiac-specific CHIP expression significantly improved cardiac function and prolonged survival in vivo by blocking DOX-induced apoptosis, inflammation and oxidative stress. The cardioprotective effects of CHIP against DOX toxicity were associated with ubiquitin-mediated degradation of p53, SHP-1 and preserved activation of ERK1/2 and STAT3 signaling pathways. These results suggest that CHIP may be a potential therapeutic target for the treatment of DOX-induced heart failure
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have