Abstract P143: Activation of GPR30 Attenuates Diastolic Dysfunction and LV Remodeling in Oophorectomized mRen2.Lewis Rats

Abstract

The incidence of diastolic dysfunction increases in women after menopause but the mechanisms involved are not completely understood. GPR30 is a novel estrogen receptor expressed in various tissues including the heart. Studies have shown that activation of GPR30 by its agonist G1, improves contractile function and reduces infarct size in isolated rat and mouse hearts subjected to ischemia/reperfusion injury and attenuates diastolic dysfunction in a salt-sensitive rat model of hypertension. We hypothesized that the activation of GPR30 by G1 protects against the development of diastolic dysfunction and cardiac hypertrophy in oophorectomized mRen2.Lewis rats, an established model that emulates the cardiac phenotype of the postmenopausal woman. Surgical bilateral oophorectomy (OVX) was performed in female mRen2.Lewis rats at 4 weeks of age, and G1 (50 or 100 µg/kg/day) was given subcutaneously via minipump starting at 13 weeks of age for 2 weeks. Both doses of G1 significantly improved lusitropic function and structure, independent of changes in blood pressure. Compared to vehicle-treated OVX rats, G1 reduced the tissue Doppler-derived index of left ventricular filling pressure (E/e’), left ventricle mass, wall thickness, and the biomarkers of hypertrophy, ANF and BNP mRNA levels. Using cultured H9c2 cardiomyocytes, in vitro studies further showed that 1) G1 inhibited angiotensin (ANG) II-induced hypertrophy, evidenced by reductions in cell size, and ANF and BNP gene expression; 2) the antagonist of GPR30, G15, inhibited estrogen’s protective effects on ANG II-induced hypertrophy; and 3) G1 induced phosphorylation of Erk and Akt. These data demonstrate the protective role of GPR30 in a model of diastolic dysfunction and cardiac hypertrophy, and provide insight into the underlying mechanisms.