Cardioprotective effects of GPER agonist in ovariectomized diabetic rats: reversing ER stress and structural changes

The incidence of diabetic cardiomyopathy (DCM) significantly increases in postmenopausal women, suggesting protective roles of estrogen. Excessive endoplasmic reticulum (ER) stress alters myocardial structure, which plays a crucial role in DCM. The G protein-coupled estrogen receptor (GPER) has been demonstrated to have cardioprotective effects, but it remains unclear whether these effects involve the amelioration of structural changes induced by ER stress. The objective of this study was to determine whether GPER can prevent cardiac structural changes by attenuating ER stress. Female ovariectomized (OVX) rats were divided into three groups: OVX, OVX + T2D, and OVX + T2D + G1. T2D was induced by a high-fat diet, and streptozotocin and G1, a GPER agonist, were administered for 6 weeks. Finally, histological changes of the myocardium were examined and the expression of sarcoplasmic reticulum calcium ATPase (SERCA2α), GRP78 as an ER stress marker, and apoptotic signalings were determined by Western blot. We observed that the induction of T2D resulted in an increased cardiac weight index, left ventricular wall thickness, and myocyte diameter. However, GPER activation reversed these changes. T2D increased cardiac protein levels of GRP78, caspase-12, and Bax, while decreasing levels of SERCA2α and Bcl-2. Nevertheless, GPER activation reduced the expression of GRP78 in OVX + T2D rats. Furthermore, GPER activation significantly reduced cardiac caspase-12 and Bax levels and increased SERCA2α and Bcl-2 expression. In conclusion, our data suggest that GPER activation ameliorates DCM by inhibiting ER stress-induced cardiac structural changes. These findings provide a new potential target for therapeutic intervention and drug discovery specifically tailored for postmenopausal diabetic women.