Lin KH, Ali A, Kuo CH, Yang PC, Kumar VB, Padma VV, Lo JF, Huang CY, Kuo WW

Advanced glycation end products (AGEs), which are highly reactive molecules resulting from persistent high-glucose levels, can lead to the generation of oxidative stress and cardiac complications. The carboxyl terminus of HSP70 interacting protein (CHIP) has been demonstrated to have a protective role in several diseases, including cardiac complications; however, the ...

Read More

role in preventing AGE-induced cardiac damages remains poorly understood. Here, we found that elevated AGE levels impaired cardiac CHIP expression in streptozotocin-induced diabetes and high-fat diet-administered animals, representing AGE exposure models. We used the TUNEL assay, hematoxylin and eosin, Masson's trichrome staining, and western blotting to prove that cardiac injuries were induced in diabetic animals and AGE-treated cardiac cells. Interestingly, our results collectively indicated that CHIP overexpression significantly rescued the AGE-induced cardiac injuries and promoted cell survival. Moreover, CHIP knockdown-mediated stabilization of nuclear factor ?B (NF?B) was attenuated by overexpressing CHIP in the cells. Furthermore, co-immunoprecipitation and immunoblot assay revealed that CHIP promotes the ubiquitination and proteasomal degradation of AGE-induced NF?B. Importantly, fluorescence microscopy, a luciferase reporter assay, electrophoretic mobility shift assay, and subcellular fractionation further demonstrated that CHIP overexpression inhibits AGE-induced NF?B nuclear translocation, reduced its binding ability with the promoter sequences of the receptor of AGE, consequently inhibiting the translocation of the receptor AGE to the cell membrane for its proper function. Overall, our current study findings suggest that CHIP can target NF?B for ubiquitin-mediated proteasomal degradation, and thereby potentially rescue AGE-induced cardiac damages.

Date: Dec. 01, 2021

View in: Pubmed Google Scholar

235422