Abstract 351: Late-life Activation of GPR30 by G1 Reverses Diastolic Dysfunction in Senescent Fischer344 x Brown Norway Female Rats
Introduction: The aged heart is characterized by impaired lusitropy and increased stiffness, and no proven pharmacologic interventions exist that limit these manifestations of left ventricular diastolic dysfunction (LVDD). G1, a selective agonist to the estrogen receptor GPR30, attenuated the effects of estrogen (E2) loss on LVDD in a hypertensive model. To extend prior studies, we determined the cardioprotective potential of chronic GPR30 activation in the female Fischer344 x Brown Norway (F344BN) rat, a normotensive aging model.
Methods and Results: Bilateral oophorectomy (OVX) or sham-operations were performed in middle- (Mid) (18 months) and Old-aged rats (27 months). At 28 months of age, Old rats were randomized to daily G1 (100 μg/kg/day, s.c.) or vehicle (VEH; soybean oil) injections (n=7 rats/group). Following 8 weeks of treatment, left ventricle (LV) mass was greater in Old vs. Mid-aged rats, independent of E2 or G1, while systolic function and LV wall thicknesses were similar among groups. Myocardial relaxation (e’) was reduced (P<0.001) and LV filling pressure (E/e’) was increased (P<0.01) in Old vs. Mid-aged rats, and this was exacerbated by OVX (P<0.01) and reversed by late-life G1 treatment. Systolic blood pressure (SBP) increased by 20% after mid-life OVX, whereas late-life E2 loss had no effect on SBP, irrespective of G1. Cardiac chymase expression was increased in E2 deficient hearts determined by Western blot and G1 modestly limited this E2/age effect.
Conclusion: Our data indicate that late-life G1 treatment reverses the detrimental effects of advanced age and E2 deficiency on diastolic function, possibly via interactions with the noncanonical cardiac renin angiotensin system.
Author Disclosures: A. Alencar: None. H. Wang: None. J. de Silva: None. M. Lin: None. X. Sun: None. L. Groban: 2. Research Grant; Significant; NIH AG-042758 (LG), NIH AG-033727 (LG).
- © 2015 by American Heart Association, Inc.