Abstract
Activated protein C (APC) is a vitamin-K dependent plasma serine protease, which functions as a natural anticoagulant to downregulate thrombin generation in the clotting cascade. APC also modulates cellular homeostasis by exhibiting potent cytoprotective and anti-inflammatory signaling activities. The beneficial cytoprotective effects of APC have been extensively studied and confirmed in a number of preclinical disease and injury models including sepsis, type-1 diabetes and various ischemia/reperfusion diseases. It is now well-known that APC modulates downstream cell signaling networks and transcriptome profiles when it binds to the endothelial protein C receptor (EPCR) to activate protease-activated receptor 1 (PAR1) on various cell types. However, despite much progress, details of the downstream signaling mechanism of APC and its crosstalk with other signaling networks are far from being fully understood. In this review, we focus on the cardioprotective properties of APC in ischemic heart disease and heart failure with a special emphasis on recent discoveries related to the modulatory effect of APC on AMP-activated protein kinase (AMPK), PI3K/AKT, and mTORC1 signaling pathways. The cytoprotective properties of APC might provide a novel strategy for future therapies in cardiac diseases.
Highlights
Protein C (PC) is a vitamin K-dependent serine protease zymogen that is primarily synthesized by the liver and circulates in plasma with a concentration of 4–5 μg/mL [1]
Upon activation by the thrombin-TM complex, activated protein C (APC) can dissociate from its membrane-bound receptor cofactor, endothelial protein C receptor (EPCR), and bind to its circulating vitamin K-dependent plasma cofactor, protein S, on a negatively charged membrane surface, to initiate its anticoagulant function by proteolytically inactivating factors Va and VIIIa, the essential procoagulant cofactors for thrombin generation in both intrinsic and extrinsic pathways of the blot clotting cascade [12,13,14]
The protective cellular signaling activity of APC is mediated through the EPCR-bound protease-activating protease-activated receptor 1 (PAR1) on endothelial or other cell types (Figure 1) [27]
Summary
Protein C (PC) is a vitamin K-dependent serine protease zymogen that is primarily synthesized by the liver and circulates in plasma with a concentration of 4–5 μg/mL [1]. The N-terminal light chain contains the gamma-carboxyglutamic acid (Gla) domain and two epidermal growth factor (EGF-1, EGF-2) domains while the C-terminal heavy chain contains the trypsin-like serine protease domain [3]. Protein C through its Gla-domain binds with a high affinity to endothelial protein C receptor (EPCR) and is converted to activated protein C (APC) through a limited proteolytic process by the thrombin-thrombomodulin (TM)- complex on the surface of endothelial cells [4,5,6]. The Gla-domain of PC has a high-affinity binding site for EPCR and this interaction on the endothelial cell surface enhances the activation of PC by the thrombin-TM complex approximately 20-fold [6]
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