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Wu 2023 Int Immunopharmacol

From Bioblast
Publications in the MiPMap
Wu F, Zhang YT, Teng F, Li HH, Guo SB (2023) S100a8/a9 contributes to sepsis-induced cardiomyopathy by activating ERK1/2-Drp1-mediated mitochondrial fission and respiratory dysfunction.

Β» Int Immunopharmacol 115:109716. PMID: 36652759 Open Access

Wu Feng,  Zhang Yan-Ting,  Teng Fei,  Li Hui-Hua,  Guo Shu-Bin (2023) Int Immunopharmacol

Abstract: Sepsis-induced cardiomyopathy (SIC) is the main complication and a leading cause of death in intensive care units. S100a8/a9 is a calcium-binding protein that participates in various inflammatory diseases; however, its role in sepsis-induced cardiomyopathy and the underlying mechanism remains to be explored. Here, septic cardiomyopathy was induced with cecal ligation and puncture (CLP) in S100a9-knockout (KO) mice lacking the heterodimer S100a8/a9 or wild-type (WT) mice administered with an S100a9-specific inhibitor Paquinimod (Paq), which prevents the binding of S100a9 toTLR4. Our results showed that S100a8/a9 expression in the heart peaked 24 h following the CLP operation, declined at 48 h and returned to baseline at 72 h. Loss of S100a9 by knockout in mice protected against CLP-induced mortality, cardiac dysfunction, myocyte apoptosis, recruitment of Mac-2+ macrophages, superoxide production, and the expression of pro-inflammatory cytokines genes compared with WT mice. Moreover, S100a9-KO significantly attenuated CLP-induced activation of the ERK1/2-Drp1 (S616) pathway, excessive mitochondrial fission, and mitochondrial respiration dysfunction. In contrast, activation of ERK1/2 with its agonist tBHQ reversed the inhibitory effects of S100a9-knockout on CLP-induced cardiomyopathy and mitochondrial dysfunction. Finally, administration of Paq to WT mice markedly prevented the CLP-induced cardiomyopathy mitochondrial fission and dysfunction compared with vehicle control. In summary, our data reveal, for the first time, that S100a8/a9 plays a critical role in mediating SIC, presumably by activating TLR4-ERK1/2-Drp1-dependent mitochondrial fission and dysfunction and highlight that blockage of S100a8/a9 may be a promising therapeutic strategy to prevent SIC in patients with sepsis. β€’ Keywords: Cardiomyopathy, ERK-Drp1, Mitochondrial fission, Mitochondrial respiratory dysfunction, S100a8/a9, Sepsis β€’ Bioblast editor: Plangger M

Labels: MiParea: Respiration, Genetic knockout;overexpression  Pathology: Cardiovascular, Myopathy, Sepsis 

Organism: Mouse  Tissue;cell: Heart  Preparation: Homogenate 

Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, NS, ROX  HRR: Oxygraph-2k