Calcitriol Prevents Isoproterenol-Induced Myocardial Fibrosis by Regulating the TGF-β1/SMAD Sensor via Binding to the Nuclear Vitamin D Receptor.

This study sought to delineate the effects of calcitriol (CAL) and clarify its role in modulating TGF-β1/SMAD-mediated myocardial fibrosis in both animal and cellular models, instigated by isoproterenol (ISO). Cardiac dysfunction was precipitated through the subcutaneous administration of ISO in BALB/c mice, followed by an assessment of the remedial effects of CAL. CAL intervention ameliorated cardiac fibrosis induced by excessive ISO exposure, which was underscored by the reduction in myocardial hypertrophy and levels of interstitial fibrosis in the cardiac tissue. ISO exposure triggered the TGF-β1/SMAD pathway and suppressed vitamin D receptor (VDR) expression; effects that were nullified by CAL therapy. Cardiac fibroblasts (CFs) were extracted from myocardial ventricles of mice, and CCK-8 assays were conducted to evaluate the viability of CFs under treatments with ISO, sTβRII (a TGF-β1 inhibitor), and CAL. The CF survival rate was increased by ISO treatment, although this was counteracted via sTβRII or CAL treatment. In this cell model, ISO treatment activated TGF-β1/SMAD pathway and downregulated VDR expression, whereas CAL cotreatment exerted a converse effect on the TGF-β1/SMAD pathway and VDR expression. VDR knockdown demonstrated its role in CAL-mediated alleviation of cell fibrosis. Our observations indicated that VDR intervention enhanced the influence of ISO on the proliferation of CFs and markedly negated the protective effects of CAL on the viability of ISO-exposed CFs. These insights unveil a pioneering role for CAL in curbing ISO-provoked cardiac fibrosis and the proliferation of CFs via the restraint of the TGF-β1/SMAD pathway through engagement with the VDR.