ELABELA-APJ-Akt / YAP Signaling Axis: A Novel Mechanism of Aerobic Exercise in Cardioprotection of Myocardial Infarction Rats.

Abstract

The aim of this study was to investigate the function and mechanisms of ELABELA (ELA) in the aerobic exercise-induced anti-apoptosis and angiogenesis of ischemic heart. The MI model of Sprague-Dawley rat was established by ligation of the left anterior descending coronary artery. MI rats underwent 5 weeks of Fc-ELA-21 subcutaneous injection and aerobic exercise training using a motorized rodent treadmill. Heart function was evaluated by hemodynamic measures. Cardiac pathological remodeling was evaluated by Masson's staining and the calculation of left ventricular weight index (LVWI). Cell proliferation, angiogenesis and YAP translocation were observed by immunofluorescence staining. Cell apoptosis was analyzed by TUNEL. Cells culture and treatment were used to elucidate the molecular mechanism of ELA. Protein expression was detected by Western blotting. Angiogenesis was observed by tubule formation test. One-way or two-way analysis of variance and Student's t test were used for statistical analysis. Aerobic exercise stimulated the endogenous ELA expression. Exercise and Fc-ELA-21 intervention significantly activated APJ-Akt-mTOR-P70S6K signaling pathway, kept more cardiomyocytes alive and increased angiogenesis, so as to inhibit the cardiac pathological remodeling and improved the heart function of MI rats. Fc-ELA-32 also had the cellular and functional cardioprotective activities in vivo. In vitro, ELA-14 peptide regulated the phosphorylation and nucleoplasmic translocation of YAP and activated the APJ-Akt signaling pathway, so as to increase the proliferation of H9C2 cells. Moreover, the anti-apoptosis and tubule formation of HUVECs were also enhanced by ELA-14, while inhibition of Akt activity weakened such effects. ELA is a potential therapeutic member that plays a key role through APJ-Akt / YAP signaling axis in aerobic exercise-induced cardioprotection of MI rats.