Wu 2023 Int Immunopharmacol
| 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. https://doi.org/10.1016/j.intimp.2023.109716 |
» 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. • Keywords: Cardiomyopathy, ERK-Drp1, Mitochondrial fission, Mitochondrial respiratory dysfunction, S100a8/a9, Sepsis • 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
2023-01
