Apelin Is a Negative Regulator of Angiotensin II-Mediated Adverse Myocardial Remodeling and Dysfunction

The apelin pathway has emerged as a critical regulator of cardiovascular homeostasis and disease. However, the exact role of pyr1-apelin-13 in angiotensin (Ang) II-mediated heart disease remains unclear. We used apelin-deficient (APLN^-/y) and apolipoprotein E knockout mice to evaluate the regulatory roles of pyr1-apelin-13. The 1-year aged APLN^-/y mice developed myocardial hypertrophy and dysfunction with reduced angiotensin-converting enzyme 2 levels. Ang II infusion (1.5 mg kg^-1 d^-1) for 4 weeks potentiated oxidative stress, pathological hypertrophy, and myocardial fibrosis in young APLN^-/y hearts resulting in exacerbation of cardiac dysfunction. Importantly, daily administration of 100 μg/kg pyr1-apelin-13 resulted in upregulated angiotensin-converting enzyme 2 levels, decreased superoxide production and expression of hypertrophy- and fibrosis-related genes leading to attenuated myocardial hypertrophy, fibrosis, and dysfunction in the Ang II-infused apolipoprotein E knockout mice. In addition, pyr1-apelin-13 treatment largely attenuated Ang II-induced apoptosis and ultrastructural injury in the apolipoprotein E knockout mice by activating Akt and endothelial nitric oxide synthase phosphorylation signaling. In cultured neonatal rat cardiomyocytes and cardiofibroblasts, exposure of Ang II decreased angiotensin-converting enzyme 2 protein and increased superoxide generation, cellular proliferation, and migration, which were rescued by pyr1-apelin-13, and Akt and endothelial nitric oxide synthase 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 cotreatment with the Akt inhibitor MK2206. In conclusion, pyr1-apelin-13 peptide pathway is a negative regulator of aging-mediated and Ang II-mediated adverse myocardial remodeling and dysfunction and represents a potential candidate to prevent and treat heart disease.