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Sodium octanoate mediates GPR84-dependent and independent protection against sepsis-induced myocardial dysfunction
Yao Lin1, Wenbin Zhang1, Xiangkang Jiang1
1Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burns of Zhejiang Province, Hangzhou 310009, China; Clinical Research Center for Emergency and Critical Care Medicine of Zhejiang Province, Hangzhou 310009, China.
Introduction:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Sodium octanoate (SO) protects against sepsis-induced myocardial dysfunction (SIMD) by reducing inflammation and oxidative stress via G protein-coupled receptor 84 (GPR84). SO also enhances cardiac energy metabolism, potentially through medium-chain acyl-CoA dehydrogenase (MCAD).
Area of Science:
- Cardiovascular Research
- Sepsis Pathophysiology
- Molecular Pharmacology
Background:
- Sepsis-induced myocardial dysfunction (SIMD) is a critical complication of sepsis.
- Identifying effective therapeutic agents for SIMD remains a significant clinical challenge.
Purpose of the Study:
- To investigate the therapeutic potential of sodium octanoate (SO) in a murine model of SIMD.
- To elucidate the underlying molecular mechanisms of SO's protective effects, including its interaction with G protein-coupled receptor 84 (GPR84) and its impact on cardiac energy metabolism.
Main Methods:
- Sepsis models were established using lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) in male mice.
- Sodium octanoate (SO) was administered at various intervals post-sepsis induction.
- GPR84 involvement was assessed via GEO data analysis, molecular docking, and experiments using DBA/2 mice.
- Cardiac energy metabolism was analyzed using metabolomics.
- Histone modifications were identified in the hearts of SO-treated septic mice.
Main Results:
- SO treatment significantly improved myocardial contractile function and reduced oxidative stress.
- SO administration upregulated GPR84 expression, and GPR84 deficiency attenuated SO's protective effects.
- SO enhanced myocardial energy metabolism by promoting acetyl-CoA synthesis and fatty acid β-oxidation, effects dependent on medium-chain acyl-CoA dehydrogenase (MCAD).
- SO induced histone acetylation, specifically at H3K123 and H3K80.
Conclusions:
- Sodium octanoate (SO) offers protection against sepsis-induced myocardial dysfunction (SIMD).
- SO's protective mechanisms involve both GPR84-mediated anti-inflammatory/antioxidant actions and GPR84-independent enhancement of cardiac energy metabolism, possibly via MCAD.
- These findings highlight SO as a potential therapeutic candidate for SIMD.
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