GPER Agonist G1, but Not Other Specific ERs Improves Diastolic Function and Attenuates Cardiac RAS Activation in Estrogen‐deficient SHR

Abstract

IntroductionLeft ventricular diastolic dysfunction (LVDD) increases the risk of developing heart failure with preserved ejection fraction (HFpEF), the predominant type of heart failure seen in women. Emerging epidemiologic evidence suggests that early menopause is positively associated with incident HF, which suggests potential protective roles of estrogens in LVDD development and progression. There are three estrogen receptors (ER) expressed in the heart, ER‐α, ER‐β, and G‐protein coupled ER (GPER). We previously found that GPER plays greater protective roles in cultured myocyte and mast cell lines than ER‐α or ER‐β, by inhibiting Ang II‐induced cell hypertrophy and serum‐induced cell proliferation, respectively. Moreover, estrogen loss‐induced LVDD in the hypertensive mRen2. Lewis rat was linked to increases in cardiac mast cell number, chymase, and Ang II. The aim of this study was to investigate how different specific agonists of estrogen receptors (ER‐α agonist PPT; ER‐β agonist DPN; and GPER agonist G‐1) influence diastolic function and cardiac renin angiotensin system (RAS) components.MethodsTwenty‐four SHR females underwent bilateral ovariectomy (OVX) at 12 weeks of age; 8 weeks post‐surgery, rats were randomized (n=6/group) to receive equipotent, daily treatments (0.24 μMol/kg/day, s.c.) of one of the above ER agonists (PPT‐ 94 μg/kg; DPN‐ 58 μg/kg; G‐1‐100 μg/kg), or vehicle (peanut oil). Following four weeks of treatment, rats were anesthetized (isoflurane) for direct blood pressure and Doppler echo measures of diastolic function, defined by e′ and E/e′. LV tissue for RAS activity and expression were evaluated. Data were analyzed by one‐way ANOVA. P<0.05 was significant.ResultsAs expected, the doses chosen for the specific ER agonists did not overtly affect blood pressure. Of the ER agonists, G‐1 had the most profound and significant impact on diastolic function, increasing myocardial relaxation (e′) and decreasing Doppler‐derived LV filling pressures (E/e′) by 53% and 24% versus control, respectively. Neither DPN nor PPT modified the altered cardiac function induced by OVX. GPER activation by G‐1 had a significant inhibitory effect on cardiac ACE activity when compared to vehicle, while the other Ang II‐forming pathway in the heart, Ang‐1–12/chymase, was not overtly altered by ER activation. All three agonists suppressed cardiac ACE2 activity. AT1R gene expression was increased in OVX‐vehicle by 47 to 61% when compared to hearts from OVX‐ERs (P=0.051) (Figure).ConclusionThese data imply that of the three estrogen receptors, GPER has a unique role in the preservation of diastolic function and modulation of the cardiac RAS, which would contribute to the protection in LVDD disease progression after estrogen loss, if pharmacologically activated.Support or Funding InformationNIH AG033727 (LG) and NIH HL 051952 (CMF and LG) INCT‐INOFAR ‐ Proc. 465249/2014‐0 (GZS and RTS) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (JS) Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq) (GZS and RTS)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.