Myocardial fibrosis is a major complication of diabetic cardiomyopathy (DCM) that is primarily caused by cardiac fibroblasts that are highly activated by persistent hyperglycemic stimulation, resulting in excessive collagen deposition. Calcium sensing receptor (CaSR) is a member of the G protein‑coupled receptor superfamily and regulates intracellular calcium concentrations, which are associated with numerous diseases, including myocardial infarction, tumors and pulmonary hypertension. However, whether CaSR participates in the pathological process of myocardial fibrosis in DCM remains unknown. The present study aimed to investigate the mechanism via which CaSR regulates high glucose (HG)‑induced cardiac fibrosis in vitro. HG treated‑cardiac fibroblast (CFs) were used and western blotting, immunoprecipitation, Cell Counting Kit‑8 assay, ELISA and transfection technology were performed to examine the role of CaSR. In the HG group, treatment with HG increased CaSR, α‑smooth muscle actin, collagen I/III and matrix metalloproteinase 2/9 expression and enhanced autophagosome generation and CF proliferation. Furthermore, CaSR activation upregulated the expression of Smad ubiquitin regulatory factor 2 (Smurf2), which led to increased intracellular Ca2+ concentrations, increased ubiquitination levels of SKI like proto‑oncogene and Smad7 and autophagy activation. Furthermore, the CaSR agonist (R568) or the CaSR inhibitor (Calhex231) and Smurf2‑small interfering RNA promoted or inhibited HG‑induced alterations, including the enhanced and weakened effects, respectively. Taken together, the results from the present study suggested that increased CaSR expression in CFs activated the Smurf2‑ubiquitin proteasome and autophagy, causing excessive CF proliferation and extensive collagen deposition, which resulted in HG‑induced myocardial fibrosis. These findings indicated a novel pathogenesis of DCM and may provide a novel strategy for the diagnosis and treatment of DCM.
Keywords: iabetic cardiomyopathy; myocardial fibrosis; calcium sensitive receptor; fibroblasts; smad ubiquitin regulatory factor 2; autophagy.