S100a8/a9 contributes to sepsis-induced cardiomyopathy by activating ERK1/2-Drp1-mediated mitochondrial fission and respiratory dysfunction.

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 24h following the CLP operation, declined at 48h and returned to baseline at 72h. 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.