Aerobic Exercise Upregulates Renal‐Derived ELABELA to Improve Myocardial Fibrosis by Activating APJ‐AMPK‐Sirt1 and Inhibiting TGFβ1‐Smad2/3 Signaling Pathways in Myocardial Infarction Mice

ELABELA (ELA) has been identified as a potential cardiovascular protective factor. However, the source of endogenous ELA and its molecular mechanism in myocardial fibrosis inhibition remain incompletely understood. Herein, we found that aerobic exercise significantly improved renal apoptosis caused by MI, inhibited inflammation, attenuated structural damage, enhanced renal function, and increased expression and secretion levels of renal ELA. Aerobic exercise stimulated the circulation of renal-derived ELA to reach the MI heart and played a protective role. Under aerobic exercise intervention, renal-specific Elabela overexpression improved myocardial pathological remodeling, decreased cardiomyocyte apoptosis, and enhanced cardiac function. Renal-specific Elabela knockdown significantly increased cardiac apoptosis, inflammation, and fibrosis levels in MI mice, leading to severe impairment of cardiac function. Following AMPK agonist intervention, ELA expression in HKC cells and culture medium increased in a concentration-dependent manner. ELA-14 significantly activated the APJ-AMPK-Sirt1 signaling pathway and inhibited Tgf-β1 transcription by regulating Sirt1 translocation, and AMPK inhibitor weakened ELA-14 function. In cultured cardiac fibroblasts (CFs), the intervention of ELA-14 significantly inhibited the activity of the TGFβ1-Smad2/3 signaling pathway, downregulated the expression of fibrosis-related proteins, increased apoptosis, and lowered the cell migration rate. After TGFβR1 inhibitor intervention, ELA-14 showed a loss of regulation of CFs. Aerobic exercise stimulates the expression of renal-derived ELA, which reaches the MI heart through blood circulation. Renal-derived ELA partly exerts its antifibrotic effects by activating the APJ-AMPK-Sirt1 pathway and inhibiting the TGFβ1-Smad2/3 signaling pathway, contributing to its cardiac protective effects.