Work

Sodium octanoate mediates GPR84-dependent and independent protection against sepsis-induced myocardial dysfunction

Year: 2024

Type: article

Abstract: This study aims to evaluate the therapeutic effects of sodium octanoate (SO), a medium-chain fatty acid salt, on SIMD in a murine model and to explore its underlying mechanisms. Male mice were subjected to sepsis models through two methods: intraperitoneal injection of lipopolysaccharide (LPS) and cecal ligation and punction (CLP). Mice received interval doses of SO every 2 hours or 4 hours for a total of six times or three times after LPS treatment. The relationship between SO and G protein-coupled receptor 84 (GPR84) was evaluated through GEO data analysis and molecular docking studies. DBA/2 mice were used to study the role of the GPR84 protein in the SO-mediated protection. Energy metabolomics was utilized to comprehensively assess the impact of SO on the levels of cardiac energy metabolic products in septic mice. histone modification identification techniques were used to further identify the specific sites of histone modification in the hearts of SO-treated septic mice. SO treatment significantly improved myocardial contractile function, restored the oxidative stress imbalance and enhanced the myocardium's resistance to oxidative injury. SO significantly promotes the expression of GPR84. The loss of GPR84 function markedly attenuates the protective effects of SO. SO enhanced myocardial energy metabolism by promoting the synthesis of acetyl-CoA and upregulating genes involved in fatty acid β-oxidation which were abolished by medium-chain acyl-CoA dehydrogenase (MCAD) knockdown. SO induced histone acetylation, particularly at H3K123 and H3K80. Our study demonstrates that SO exerts protective effects against SIMD through both GPR84-mediated anti-inflammatory and antioxidant actions and GPR84-independent enhancement of myocardial energy metabolism, possibly mediated by MCAD. Schematic illustration of the protective effect of sodium octanoate to treat sepsis-induced myocardial dysfunction via GPR84-mediated signal transduction and MCAD-mediated energy metabolism promotion. ● Early administration of sodium octanoate (SO) following sepsis induction can enhance cardiac function, reduce myocardial damage and prolong survival in septic mice through both GPR84-dependent protective effects and GPR84-independent promotion of energy metabolism. ● This study demonstrates that, under the high-inflammatory state of sepsis, the activation of GPR84 by medium-chain fatty acids can inhibit the NF-κB and MAPK pathways, thereby modulating the inflammatory response and alleviating myocardial oxidative stress injury. ● Sodium octanoate improves myocardial cell energy and exerts its epigenetic modification capabilities through MCAD.

Source: Biomedicine & Pharmacotherapy

DOI: 10.1016/j.biopha.2024.117455