Dataset Information

MicroRNA-410-3p Binds to TLR2 and Alleviates Myocardial Mitochondrial Dysfunction and Chemokine Production in LPS-Induced Sepsis.

ABSTRACT: Mitochondrial dysfunction and chemokine production have been reported to be involved in the pathogenesis of sepsis. Our initial bioinformatics analysis identified differentially expressed TLR2 in sepsis and the upstream regulatory microRNA-410-3p (miR-410-3p). Hence, the current study was performed to characterize the potential mechanism by which miR-410-3p modulates mitochondrial dysfunction and chemokine production in lipopolysaccharide (LPS)-induced mice in vivo and cardiomyocytes in vitro. Next, we identified that miR-410-3p was downregulated, while TLR2 was upregulated in LPS-induced mice and cardiomyocytes. In addition, miR-410-3p was confirmed to target and inhibit the TLR2 expression. Thereafter, gain- or loss-of-function experiments were conducted to investigate the effect of miR-410-3p and TLR2 on mitochondrial function and chemokine production. TLR2 knockdown or miR-410-3p overexpression was found to alleviate mitochondrial membrane damage and mitochondrial swelling, in addition to augmenting the levels of adenosine triphosphate, mitochondrial membrane potential, and the expression levels of CCL7, CCL5, CXCL1, and CXCL9 in vivo and in vitro. In conclusion, miR-410-3p-mediated TLR2 inhibition alleviated mitochondrial dysfunction and reduced chemokine production in LPS-induced experimental sepsis. Therefore, the overexpression of miR-410-3p may represent a potential strategy for the treatment of sepsis-induced myocardial injury.

SUBMITTER: Zuo T

PROVIDER: S-EPMC7516191 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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MicroRNA-410-3p Binds to TLR2 and Alleviates Myocardial Mitochondrial Dysfunction and Chemokine Production in LPS-Induced Sepsis.

Zuo Tongkun T Tang Qing Q Zhang Xiangcheng X Shang Futai F

Molecular therapy. Nucleic acids 20200725

Mitochondrial dysfunction and chemokine production have been reported to be involved in the pathogenesis of sepsis. Our initial bioinformatics analysis identified differentially expressed TLR2 in sepsis and the upstream regulatory microRNA-410-3p (miR-410-3p). Hence, the current study was performed to characterize the potential mechanism by which miR-410-3p modulates mitochondrial dysfunction and chemokine production in lipopolysaccharide (LPS)-induced mice <i>in vivo</i> and cardiomyocytes <i>i ...[more]

PMID: 33230433

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Project description:IntroductionSevere sepsis is characterised by intravascular or extravascular infection with microbial agents, systemic inflammation and microcirculatory dysfunction, leading to tissue damage, organ failure and death. The growth factor angiopoietin (Ang-1) has therapeutic potential but recombinant Ang-1 tends to aggregate and has a short half-life in vivo. This study aimed to investigate the acute effects of the more stable Ang-1 variant matrilin-1-angiopoietin-1 (MAT.Ang-1) on the function of the microcirculation in an experimental model of sepsis, and whether any protection by MAT-Ang-1 was associated with modulation of inflammatory cytokines, angiogenic factors or the endothelial nitric oxide synthase (eNOS)-Akt and vascular endothelial (VE)-cadherin pathways.MethodsAluminium window chambers were implanted into the dorsal skinfold of male C3H/HeN mice (7 to 10 weeks old) to expose the striated muscle microcirculation. Endotoxemia was induced by intraperitoneal injection of lipopolysaccharide (LPS, 1 mg/kg at 0 and 19 hours). MAT.Ang-1 was administered intravenously 20 hours after the onset of sepsis. Microcirculatory function was evaluated by intravital microscopy and Doppler fluximetry.ResultsEndotoxemia resulted in macromolecular leak, which was ameliorated by MAT.Ang-1 post-treatment. LPS induced a dramatic reduction in tissue perfusion, which was improved by MAT.Ang-1. Proteome profiler array analysis of skeletal muscle also demonstrated increased inflammatory and reduced angiogenic factors during endotoxemia. MAT.Ang-1 post-treatment reduced the level of IL-1β but did not significantly induce the expression of angiogenic factors. MAT.Ang-1 alone did not induce leak or increase angiogenic factors but did reduce vascular endothelial growth factor expression in controls.ConclusionAdministration of MAT.Ang-1 after the onset of sepsis protects the microcirculation from endotoxemia-induced vascular dysfunction through reducing inflammation but without pro-angiogenic actions, thus representing a novel, potential pharmacotherapeutic agent for the treatment of sepsis.

Project description:Background and aimsThe triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD.MethodsThe relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9-/- mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice.ResultsIn sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9-/- mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9-/- mice, confirming target specificity.ConclusionElevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis.

Dataset Information

MicroRNA-410-3p Binds to TLR2 and Alleviates Myocardial Mitochondrial Dysfunction and Chemokine Production in LPS-Induced Sepsis.

Publications

MicroRNA-410-3p Binds to TLR2 and Alleviates Myocardial Mitochondrial Dysfunction and Chemokine Production in LPS-Induced Sepsis.

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