Unraveling the Mechanisms of S100A8/A9 in Myocardial Injury and Dysfunction

Abstract

S100A8 and S100A9, which are prominent members of the calcium-binding protein S100 family and recognized as calprotectin, form a robust heterodimer known as S100A8/A9, crucial for the manifestation of their diverse biological effects. Currently, there is a consensus that S100A8/A9 holds promise as a biomarker for cardiovascular diseases (CVDs), exerting an influence on cardiomyocytes or the cardiovascular system through multifaceted mechanisms that contribute to myocardial injury or dysfunction. In particular, the dualistic nature of S100A8/A9, which functions as both an inflammatory mediator and an anti-inflammatory agent, has garnered significantly increasing attention. This comprehensive review explores the intricate mechanisms through which S100A8/A9 operates in cardiovascular diseases, encompassing its bidirectional regulatory role in inflammation, the initiation of mitochondrial dysfunction, the dual modulation of myocardial fibrosis progression, and apoptosis and autophagy. The objective is to provide new information on and strategies for the clinical diagnosis and treatment of cardiovascular diseases in the future.

Keywords: S100A8/A9; biomarker; inflammation; mitochondria; myocardial damage.

Figure 1

The role of S100A8/A9 in inflammation during cardiac injury. When the heart undergoes inflammation, neutrophils aggregate and activate, releasing a substantial amount of S100A8/A9. These proteins bind to TLR4 or RAGE, activating the NF-κB and MAPK pathways, which leads to an increased recruitment of inflammatory cells. Necrotic debris in infarcted areas is cleared via phagocytosis by pro-inflammatory Ly6Chigh monocytes, which differentiate into pro-inflammatory macrophages (M1). As Ly6Clow monocytes differentiate into anti-inflammatory macrophages (M2), they promote cardiac repair after MI by expressing repair-promoting cytokines, such as IL-10, VEGF, and TGF-β1. Following MI, cardiac repair begins with the clearance of apoptotic neutrophils; however, the precise temporal juncture between cardiac inflammation and repair remains elusive. TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.

Figure 2

A model showing how S100A8/A9 causes myocardial disfunction by triggering mitochondrial dysfunction. S100A8/A9 proteins decrease the expression of the NDUF gene, which then inhibits mitochondrial complex I activity through a pathway involving TLR4/Erk. This process suppresses the signaling of PGC-1α/NRF1. Treating with an antibody that neutralizes S100A9 markedly reduces injury caused by ischemia/reperfusion and enhances cardiac function. ETC com I, electron transport chain (ETC) complex I; NDUFs, ETC complex I genes; PGC-1α/NRF1, Pparg coactivating factor 1 alpha/nuclear respiratory factor 1.

Figure 3

Summary of possible mechanisms of action of S100A8/A9 on cardiomyocytes. Following its passive or active release from neutrophils or monocytes, S100A8/A9 exerts its roles mainly by binding to TLR4 and RAGE. In aggravating myocardial injury, it is associated with mechanisms that drive the progression of inflammation, cause mitochondrial dysfunction, exacerbate the progression of myocardial fibrosis, and lead to autophagy and apoptosis. In cardioprotection, S100A8/A9 can play a role through the anti-inflammatory and attenuating cardiomyocyte fibrosis pathways. NRF1, nuclear respiratory factor 1; PGC-1α, Pparg coactivator 1 alpha; TLR4, Toll-like receptor 4; RAGE, receptor for advanced glycation end products; FGF2-SOX9, fibroblast growth factor 2-SOX9; MAPK, mitogen-activated protein kinase; P13K-AKT, phosphoinositide 3-kinase; ROS, reactive oxygen species.