Hydrogen Sulfide Attenuated Sepsis-Induced Myocardial Dysfunction Through TLR4 Pathway and Endoplasmic Reticulum Stress.

Yu-Hong Chen,Yu-Ming Wu,Sheng Jin,Xu Teng,Zhen-Jie Hu,Dan-Yang Tian

doi:10.3389/fphys.2021.653601

Abstract

Aims: We examined the change in endogenous hydrogen sulfide (H2S) production and its role in sepsis-induced myocardial dysfunction (SIMD).Results: Significant elevations in plasma cardiac troponin I (cTnI), creatine kinase (CK), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were noted in SIMD patients, whereas left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and plasma H2S were significantly decreased relative to those in the controls. Plasma H2S was linearly related to LVEF and LVFS. Subsequently, an SIMD model was developed in mice by injecting lipopolysaccharide (LPS), and NaHS, an H2S donor, was used to elucidate the pathophysiological role of H2S. The mice showed decreased ventricular function and increased levels of TNF-α, IL-1β, cTnI, and CK after LPS injections. Toll-like receptor (TLR) 4 protein and endoplasmic reticulum stress (ERS) proteins were over expressed in the SIMD mice. All of the parameters above showed more noticeable variations in cystathionine γ-lyase knockout mice relative to those in wild type mice. The administration of NaHS could improve ventricular function and attenuate inflammation and ERS in the heart.Conclusion: Overall, these findings indicated that endogenous H2S deficiency contributed to SIMD and exogenous H2S ameliorated sepsis-induced myocardial dysfunction by suppressing inflammation and ERS via inhibition of the TLR4 pathway.

Highlights

Sepsis is the predisposing factor of organ failure and has a considerable mortality rate in critical care patients (Singer et al, 2016)
The cardiac troponin I, creatine kinase (CK), tumor necrosis factor-α (TNF-α), and IL-1β levels in plasma were significantly higher in the Sepsis-induced myocardial dysfunction (SIMD) patients than in the controls (Figures 1D–G, respectively)
We found that the expressions of CCAAT/enhancer-binding protein- homologous protein (CHOP), caspase-12, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1α (IRE-1α) were obviously higher in the LPS group than in the Control group, which were significantly reduced by subsequent treatment with 50 μmol/kg NaHS (Figures 5E,F,H–K)

Summary

Introduction

Sepsis is the predisposing factor of organ failure and has a considerable mortality rate in critical care patients (Singer et al, 2016). The heart, as a circulatory system component, is a key target organ for injury in sepsis. Sepsis-induced myocardial dysfunction (SIMD) was observed in approximately half of the patients with sepsis, and associated with adverse outcomes and increased mortality (Frencken et al, 2018). H2S Attenuated Sepsis-Induced Myocardial Dysfunction (Liu et al, 2017). Toll-like receptors (TLRs), TLR4, increase inflammatory cytokines expression, especially tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), which may lead to myocardial depression. Several studies have confirmed that TNF-α and IL-1β were associated with myocardial injury, and inhibition of TLR4 improved myocardial dysfunction (Zhao et al, 2016; Tan et al, 2019)

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Discussion

Conclusion