Abstract 312: Activation of GPR30 Attenuates Cardiac Injury in the Ovariectomized Diabetic mRen2.Lewis Rat

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Our previous study demonstrated that the exacerbation of hypertension as well as alterations in the angiotensin II type 1 receptor (AT1) and endothelial nitric oxide synthase (eNOS) pathways were associated with the development of cardiac remodeling in the diabetic, ovariectomized (OVX-D) mRen2.Lewis rats. The present study evaluated the cardiovascular effects of G-1, a selective agonist of the estrogen receptor GPR30, in insulin- and estrogen-depleted mRen.Lewis rats. Hemizygous littermates were divided into 3 groups: intact controls (C); OVX-D, and OVX-D treated with G1 (G-1). Ovariectomy was performed at 10 weeks of age and diabetes subsequently induced at 11 weeks with streptozotocin (65 mg/kg). G-1 was given by osmotic minipump implanted 2 days after STZ injection (0.2 mg/kg/day; ip). After four weeks blood pressure was measured and heart removed for analysis of AT1 receptor and eNOS protein expression as well as immunohistochemical identification of GPR30. Left ventricle (LV) wet weight was measured and cardiac tissue fibrosis was analyzed from the LV sections stained with picrosirius red. Immunohistochemical staining for GPR30 was evident in both coronary vessels and cardiac myocyte of the OVX-D rats. Chronic treatment with G1 decreased the systolic blood pressure (C: 142 ± 3; OVX-D: 184 ± 3*; G-1: 167 ± 6* # mmHg; *p<0.05 vs C; # p<0.05 vs OVX-D) and the incidence of microinfractions but did not reduce LV weight of OVX-D mRen2.Lewis rats (C: 0.57 ± 0.01; OVX-D: 0.62 ± 0.02*; G-1: 0.63 ± 0.01*g). G-1 treatment was associated with an increase in the cardiac expression of eNOS (C: 100 ± 6%; OVX-D: 59 ± 2%*; G-1: 86 ± 2% # ) but the agonist did not alter cardiac AT1 receptor expression (C: 100 ± 14%; OVX-D: 163 ± 11%*; G-1: 174 ± 9%*). We detected no change in uterine weight of the OVX-D rats treated with G-1 suggesting no crossover of the agonist with the steroid receptors ERα or ERβ (C: 0.68 ± 0.07; OVX-D: 0.14 ± 0.01*; G-1: 0.14 ± 0.01*g). In conclusion, the present study suggests that selective activation of a novel GPR30 receptor may attenuate cardiac injury in estrogen- and insulin-depleted mRen2.Lewis rats by reducing blood pressure and preserving eNOS pathway.