A1156 Cardioprotective effects of Apelin-13 on aging- and angiotensin II-mediated adverse myocardial injury and dysfunction in hypertensive mice

Abstract

Objectives: The apelin-APJ system and angiotensin (Ang) II-AT1 pathways have emerged as potent regulators of blood pressure and cardiovascular function. However, the interaction between the apelin and Ang system in myocardial injury remains unclear. Methods: The C57/B6 wildtype (WT), apolipoprotein E (ApoE) knockout (KO) and apelinKO mice were randomized to receive either Ang II (1.5 mg.kg-1.d-1) osmotic minipump and /or 100 ug/kg pyr1-apelin-13 for 4 weeks. Results: 1-year aged APLN-/y mice developed increased myocardial hypertrophy and fibrosis with downregulation of ACE2 levels. Importantly, pyr1-apelin-13 reversed Ang II-mediated hypertension, myocardial apoptosis and pathological hypertrophy in both WT and ApoEKO mice. Ang II-induced cardiac fibrosis, dysfunction and altered myocardial ultrastructure were aggravated in the ApoEKO mice which were prevented by pyr1-apelin-13. Importantly, pyr1-apelin-13 attenuated Ang II-mediated pathological effects in ApoE-null hearts associated with increased levels of ACE2 and p-ERK1/2. In cultured neonatal rat cardiomyocytes and cardiofibroblasts, exposure of Ang II decreased ACE2 protein and increased superoxide generation, cellular proliferation and migration, which were rescued by pyr1-apelin-13, Akt and eNOS agonist stimulation. The increased superoxide generation and apoptosis in cultured cardiofibroblasts in response to Ang II were strikingly prevented by pyr1-apelin-13 which was partially reversed by co-treatment with the Akt inhibitor MK2206. Conclusion: Our data provide definitive evidence for cardioprotective roles of pyr1-apelin-13 in aging- and Ang II-mediated pathological remodeling, myocardial fibrosis and dysfunction. Targeting the apelin-APJ pathway represents a novel therapeutic approach against hypertension.