S100 proteins in cardiovascular diseases

Abstract

Cardiovascular diseases have become a serious threat to human health and life worldwide and have the highest fatality rate. Therefore, the prevention and treatment of cardiovascular diseases have become a focus for public health experts. The expression of S100 proteins is cell- and tissue-specific; they are implicated in cardiovascular, neurodegenerative, and inflammatory diseases and cancer. This review article discusses the progress in the research on the role of S100 protein family members in cardiovascular diseases. Understanding the mechanisms by which these proteins exert their biological function may provide novel concepts for preventing, treating, and predicting cardiovascular diseases.

Keywords: Cardiovascular diseases; RAGE; S100 proteins; TLR-4.

Fig. 1

The general structure of S100 proteins. A Apo-S100 protein shown with a purple subunit and a yellow subunit. S100 proteins are regulated by Ca²⁺ binding (red circles), which allows them to function as Ca²⁺ sensors that can convert changes in intracellular Ca²⁺ levels into a cellular response. Ca²⁺ binding induces a conformational rearrangement that exposes a hydrophobic cleft, which is necessary for the S100 protein to bind its cellular targets (green) and elicit a physiological response. B The mode of S100A1 action demonstrates the calcium-dependent conformational change that is helpful for S100A1 to interact with its target molecules

Fig. 2

Function of S100A1 in cardiomyocytes and endothelial cells. A In cardiomyocytes, S100A1 regulates calcium homeostasis by enhancing SERCA2 activity and controlling the function of RyR2. The regulation of RyR2 by S100A1 reduces Ca²⁺ leakage from the sarcoplasmic reticulum in diastole and increases Ca²⁺ release from the sarcoplasmic reticulum in systole. S100A1 also regulates sarcomere stiffness and Ca²⁺ response. Moreover, S100A1 regulates the mitochondrial function and energy metabolism of cardiomyocytes and inhibits their apoptosis. Finally, S100A1 inhibits ventricular remodeling and prevents arrhythmia. B The main role of S100A1 in endothelial cells is the control of Ca²⁺ uptake and release from the endoplasmic reticulum and the regulation of NO balance

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

Fig. 4

S100A12 is closely related to the onset and development of inflammation. The interaction of S100A12 with RAGE activates inflammatory cells such as macrophages and lymphocytes. When macrophages absorb lipids, they form foam cells that participate in the formation of atherosclerotic lesions. In addition, the interaction of S100A12 with TLR4 activates monocytes and induces an inflammatory response. Activated NF-κB and MAPK pathways produce a large number of pro-inflammatory cytokines (TNF-α, IL-1β) and adhesion molecules (VCAM-1, ICAM-1) and downregulate the expression of the anti-apoptotic protein Bcl-2 and upregulate the expression of pro-apoptotic proteins Bax, caspase-3, and caspase-9, leading to cell apoptosis and vascular calcification

Fig. 5

VEGF secreted by cardiomyocytes activates the response of the RAGE receptor to S100B, promotes the release of fibroblast growth factor, and induces the proliferation of cardiac fibroblasts. In addition, the interaction between S100B and RAGE activates p53 and initiates apoptosis through the MEK-ERK1/2 pathway