Fig. 3

Angiotensin II stimulates neutrophils to produce large amounts of S100A8 and S100A9. The S100A8/A9 complex activates transmembrane RAGE receptors on the surface of cardiac fibroblasts, stimulates cell migration, and activates the inflammatory response by generating significant amounts of cytokines, such as IL-1, IL-6, IL-12, and TNF-α, and chemokines, such as CXCL-1, CXCL-2, CCL-2, and CCL-3. S100A8/A9 activates TLR-4 receptors in cardiomyocytes and inhibits NDUFs genes that promote the formation of ETC complex I by suppressing PGC-1/NRF1. The resulting inhibition of ETC complex I activity causes mitochondrial dysfunction and eventually cell death. In addition, S100A8 and S100A9 reduce Ca²⁺ flux in cardiomyocytes and induce NF-κB expression by inhibiting SERCA2a activity via transmembrane RAGE receptors. Also, lipopolysaccharide activates TLR-4 receptors in cardiomyocytes, resulting in upregulation of S100A8 and S100A9 expression mediated by MyD88 and NF-κB