S100A8 and S100A9 in cardiovascular biology and disease

Abstract

There is recent and widespread interest in the damage-associated molecular pattern molecules S100A8 and S100A9 in cardiovascular science. These proteins have a number of interesting features and functions. For example, S100A8 and S100A9 (S100A8/A9) have both intracellular and extracellular actions, they are abundantly expressed in inflammatory and autoimmune states, primarily by myeloid cells but also by other vascular cells, and they modulate inflammatory processes, in part through Toll-like receptor 4 and the receptor for advanced glycation end products. S100A8/A9 also have anti-inflammatory and immune regulatory actions. Furthermore, increased plasma levels of S100A8/A9 predict cardiovascular events in humans, and deletion of these proteins partly protects Apoe(-)(/)(-) mice from atherosclerosis. Understanding the roles of S100A8 and S100A9 in vascular cell types and the mechanisms whereby these proteins mediate their biological effects may offer new therapeutic strategies to prevent, treat, and predict cardiovascular diseases.

Figure 1. Schematic representation of the potential effects of S100A8/A9 in atherosclerosis

In neutrophils, S100A8/A9 promote expression of inflammatory mediators, phagocytosis, and migration through the vascular endothelium. Likewise, in monocytes, S100A8/A9 stimulate migration and an inflammatory phenotype. Endothelial cells express S100A8/A9 following exposure to inflammatory stimuli, and when added exogenously, these proteins promote adhesion molecule expression, chemokine expression, and permeability of the endothelial layer, all of which may promote atherogenesis. Macrophages express and release significantly less S100A8/A9 than do DCs. S100A8/A9 suppress DC differentiation, antigen presentation, and release of inflammatory mediators. S100A8/A9 promote proliferation of VSMCs, which might contribute to fibrous cap formation. Thus, S100A8/A9 affect the major cell types involved in atherosclerosis, and these proteins have cell type-selective effects. The relative contribution of these cell types during different stages of lesion progression is likely to govern the overall effect of S100A8/A9 inhibition.

Figure 2. S100A8/9 differentially modify phenotypic states of neutrophils, monocytes/macrophages, and dendritic cells through extracellular and intracellular mechanisms

The effects of S100A8/A9 on processes involved in inflammation, and the proposed signaling pathways are shown for different myeloid-derived cells. (E), extracellular effects; (I), intracellular effects of S100A8/A9