Cereblon-induced endoplasmic reticulum stress in diabetic cardiomyopathy

抄録

Type 2 Diabetes Mellitus (T2DM) is characterized by insulin dysfunction, brought about by chronic hyperglycemia. The endoplasmic reticulum (ER) has been implicated in diabetic cardiomyopathy (DCM) progression. This study aimed to determine a novel target for new therapeutic modality to address T2DM-induced cardiomyopathy. Cereblon (CRBN) has been found to function in cardiovascular disease and so, this study further elucidated how CRBN can induce cardioprotection via attenuation of ER stress response in T2DM. 11-week-old C57BL/6 and CRBN knockout mice were fed with high fat diet for 4 weeks and administered with streptozotocin to induce T2DM in vivo after which samples were collected when mice reached 20 weeks of age. Mouse cardiac fibroblasts treated with high glucose and palmitic acid were used to induce ER stress in vitro. Pharmacologic and genetic CRBN knockdown was also done on in vitro T2DM mode using TD-165, a PROTAC-based CRBN degrader, and shCRBN adenovirus, respectively. Western blot and RT-PCR analyses were used to assess ER stress protein and RNA expression under T2DM conditions. Higher CRBN levels were observed in the T2DM model in vivo and in vitro. ER stress proteins were modulated upon knockdown of CRBN, both genetic and pharmacological, suggesting the possible interaction of CRBN with ER stress proteins. Additionally, fibrosis was also alleviated upon knockdown of CRBN. Knockdown of CRBN regulated the quantitative expression of ER stress proteins and RNA indicating that CRBN may be used as a novel target in alleviating ER stress in T2DM.