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

Abstract

PurposeThe aim of this study was to investigate the function and mechanisms of ELABELA (ELA) in the aerobic exercise-induced antiapoptosis and angiogenesis of ischemic heart.MethodsThe myocardial infarction (MI) model of Sprague–Dawley rat was established by the ligation of the left anterior descending coronary artery. MI rats underwent 5 wk 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. Cell proliferation, angiogenesis, and Yes-associated protein (YAP) translocation were observed by immunofluorescence staining. Cell apoptosis was analyzed by TUNEL. Cell 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 ANOVA and Student’s t-test were used for statistical analysis.ResultsAerobic 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 antiapoptosis and the tubule formation of HUVECs were also enhanced by ELA-14, whereas the inhibition of Akt activity weakened such effects.ConclusionsELA is a potential therapeutic member that plays a key role through APJ-Akt/YAP signaling axis in aerobic exercise-induced cardioprotection of MI rats.

The roles of Hippo/YAP signaling pathway in physical therapy

“…Xi et al observed that aerobic training played a crucial role in inhibiting the cardiac pathological remodeling and safeguarding the myocardium in rats with myocardial infarction. Mechanically, by promoting proliferation of H9C2 cells, aerobic training kept more cardiomyocytes alive and increased angiogenesis through regulating YAP phosphorylation and nuclear translocation to activate the APJ-Akt signaling pathway [65].…”

Emerging roles of ferroptosis in pulmonary fibrosis: current perspectives, opportunities and challenges

“…Aside from the molecules mentioned above, several other compounds with anti-ferroptotic properties have demonstrated antifibrotic effects in various organs besides the lungs, and hold promise for potential therapeutic application in PF. Elabela-32 (ELA-32), an mTOR agonist, has demonstrated efficacy in mitigating myocardial infarction and attenuating myocardial fibrosis in rat models [190]. Furthermore, it has exhibited the ability to reverse TGF-β1-induced epithelial-mesenchymal transition (EMT) in human peritoneal mesothelial cells (HPMC) (123) and pulmonary vascular remodeling induced by pulmonary arterial hypertension (PAH) [191].…”