Fibroblast Growth Factor 18 Regulates Mitochondrial Function to Alleviate Myocardial Ischemia-Reperfusion Injury in Rats

The purpose of this work was to examine the function of fibroblast growth factor 18 (FGF18) in rat myocardial ischemia-reperfusion injury (MIRI) and elucidate its relationship to mitochondrial function through the Sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1 (SIRT1/PGC-1α) pathway. To evaluate myocardial infarct size, pathological alterations, cardiomyocyte injury, mitochondrial state, oxidative stress, and SIRT1/PGC-1α protein expression, FGF18-knockdown and FGF18-overexpression rat MIRI models were created. H9c2 cardiomyocytes were used to create an in vitro hypoxia-reoxygenation (H/R) model, and FGF18-overexpressing H9c2 cells were given the SIRT1 inhibitor EX-527. We detected the effects of FGF18-mediated regulation of the SIRT1/PGC-1α pathway on H/R-induced alterations in H9c2 cells, including cell viability, mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential, apoptotic rate, and the protein expression of FGF18, SIRT1, PGC-1α, and mitofusin 1 (Mfn1). Furthermore, we performed a protein immunoprecipitation (IP)-protein acetylation assay to determine whether FGF18 influences the acetylation level of PGC-1α through the regulation of SIRT1. Results showed that FGF18 overexpression upregulated SIRT1/PGC-1α/Mfn1 expression, improved mitochondrial function, reduced oxidative stress, and enhanced H9c2 survival under H/R, while FGF18 knockdown had opposite effects. Moreover, FGF18 overexpression inhibited H/R-induced PGC-1α acetylation, and SIRT1 inhibition abrogated FGF18-mediated protective effects. Collectively, FGF18 attenuates rat myocardial MIRI by alleviating oxidative stress and regulating mitochondrial homeostasis through SIRT1-mediated deacetylation of PGC-1α.