Pretreatment of GPER agonist G1 protects male mice from septic-induced cardiomyopathy via increasing mitochondria fusion against dysregulated linoleic acid / arachidonic acid metabolism

Background G protein-coupled estrogen receptor (GPER) are involved in the sex dimorphism of sepsis- induced cardiomyopathy (SIC), but its protective role and metabolic mechanism in male remain unclear. We investigated whether GPER could attenuate SIC by improving metabolic remodeling. Methods Male mice were subjected to cecal ligation and puncture (CLP) surgery to induce SIC with pretreatment of GPER agonist G1 or without. Results G1 mitigate CLP-induced cardiac dysfunction, inflammatory injury and hypertrophy in male mice. G1 upregulated the expression of mitochondrial fusion proteins (OPA1 and MFN2) and DRP1-ser 637 which improved stress-induced mitochondria fragmentation. Untargeted metabolomics showed G1 pretreatment down-regulated the widely up-regulated metabolism and other activated biological processing after CLP, including the metabolism of lipid, amino acid and nucleotide, membrane transport (ABC transporters) and signal transduction (mTOR signaling pathway). Specifically, G1 modulated the linoleic acid (LA) metabolism (rich factor = 0.071, P = 0.0035) and arachidonic acid (AA) metabolism (rich factor = 0.024, P = 0.0236), which might attribute to its anti-inflammatory effect. Conclusions GPER confers cardiac protection from structure and function injury after CLP through increasing mitochondrial fusion. Untargeted metabolomics unravels an intriguing link between GPER activation and cardiac metabolism and highlights its modulation on dysregulated metabolism, especially on homeostasis of LA/AA metabolism.