Equivalence of G1/GPER Monotherapy Compared with Dual Administration of G1 and Lisinopril in Preventing Diastolic Dysfunction due to Estrogen Loss in SHR
Authors: Sun Xuming , Wright Kendra N , Hodge Hunter S , Ahmad Sarfaraz , Varagic Jasmina , Wang Hao , Ferrario Carlos M , Groban Leanne 
Published: June 2021

IntroductionThe increased prevalence of heart failure with preserved ejection fraction (HFpEF) in women after menopause is linked to estrogen deficiency‐induced increases in systolic hypertension and chamber stiffness, with corresponding reductions in myocardial relaxation. New evidence reveals that the anti‐remodeling and lusitropic benefits of estrogen in preventing diastolic dysfunction, the precursor of HFpEF, may be due, in part, to a GPER‐mediated suppression of cardiac ACE activity. The aim of this study was to investigate the effects of monotherapy with the GPER specific agonist G1 against ACE inhibition on preserving diastolic function after estrogen loss and compare it to combination therapy, G1 plus lisinopril, in a hypertensive rodent model.MethodsTwenty SHR females underwent bilateral ovariectomy (OVX) while 5 SHRs received sham surgery at 11–12 weeks of age; 8 weeks post‐surgery, rats were randomized (n=5/group) to receive either a subcutaneous blank (vehicle) or G‐1 pellet (100 mg/kg) plus drinking water with or without lisinopril (Lis)(10 mg//kg, PO). Body weight and tail cuff blood pressures were recorded weekly and water consumption was measured daily. Following 2 months of treatment, rats were lightly anesthetized (Isoflurane) for echocardiographic measures of cardiac function and structure. LV tissue RAS activity was evaluated by HPLC. Data were analyzed by ANOVA. P<0.05 was considered significant.ResultsLisinopril and combination therapy with Lis + G1 reversed OVX‐related increases in blood pressure (Fig. 1) and reduced LV weight/tibia length. Monotherapy with G1 had no overt impact on either parameter. Even so, profound and significant increases in myocardial relaxation (e’) were observed with G1 monotherapy and combination G1 + Lis therapy when compared to vehicle and Lis‐treatments alone (Fig. 2). Compared to vehicle, relative wall thicknesses (RWT) were also significantly reduced by monotherapy with G1 (36% reduction, P < 0.0001), and this occurred to an extent that was modestly greater than that resulting from lisinopril monotherapy (20% reduction, P <0.05). Lisinopril did not add to G1's benefit on RWT. Moreover, G1 had the greatest suppressive effect on cardiac ACE activity when compared to combination therapy and ACE inhibition alone (Fig. 3).ConclusionsMonotherapy with G1 was as effective at preventing OVX‐induced impairments in myocardial relaxation and increases in wall thickness as combination therapy with G1+ Lisinopril, and was better than ACE inhibition alone in the OVX‐SHR. The study reveals a novel action of G1 in suppressing cardiac ACE activity by a blood pressure‐independent mechanism and ACE‐mediated angiotensin II formation.Support or Funding InformationAG033727 (LG); P01‐HL051952 (LG, CMF)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.