Activated protein C prevents inflammation yet stimulates angiogenesis to promote cutaneous wound healing

Abstract

Activated protein C (APC) is a serine protease that plays a central role in physiological anticoagulation, and has more recently been shown to be a potent anti-inflammatory mediator. Using cultured human cells, we show here that APC up-regulates the angiogenic promoters matrix metalloproteinase-2 in skin fibroblasts and umbilical vein endothelial cells, vascular endothelial growth factor in keratinocytes and fibroblasts, and monocyte chemoattractant protein-1 in fibroblasts. In the chick embryo chorioallantoic membrane assay, APC promoted the granulation/remodeling phases of wound healing by markedly stimulating angiogenesis as well as promoting reepithelialization. In a full-thickness rat skin-healing model, a single topical application of APC enhanced wound healing compared to saline control. APC-treated wounds had markedly more blood vessels on day 7 and a significantly lower infiltration of neutrophils at days 4 and 7. The broad spectrum matrix metallo-proteinase, GM6001, prevented the ability of APC to promote wound healing. In summary, our results show that APC promotes cutaneous wound healing via a complex mechanism involving stimulation of angiogenesis and inhibition of inflammation. These unique properties of APC make it an attractive therapeutic agent to promote the healing of chronic wounds.

Activation of cartilage matrix metalloproteinases by activated protein C

“…Activated protein C was initially identified as an anticoagulant; however, recent studies have revealed that it has important antiinflammatory properties (4). We have now shown that APC may be detrimental to articular cartilage through its promotion of the degradation of aggrecan and collagen by activating MMPs.…”

“…In addition to its anticoagulant role, APC has significant antiinflammatory properties, such as decreasing proinflammatory cytokine synthesis and reducing leukocyte recruitment (4). In vivo, APC protects against the lethal effects of endotoxemia in animal models and suppresses lipopolysaccharide-induced tumor necrosis factor ␣ (TNF␣) production (5).…”

“…In vivo, APC protects against the lethal effects of endotoxemia in animal models and suppresses lipopolysaccharide-induced tumor necrosis factor ␣ (TNF␣) production (5). APC accelerates cuta-neous wound healing due to increased cell proliferation and migration, and it attenuates keratinocyte apoptosis (4). These antiinflammatory responses of APC are EPCRdependent and are largely mediated by cleavage of the protease-activated receptors (PARs) (6).…”

Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1

“…Past studies have indicated that APC is either activating proteases that degrade the extracellular matrix [27,28] and/or activating receptor(s) that initiate signaling pathways to increase invasion and chemotaxis. Other studies have shown that the ability of APC to interact with EPCR and PAR-1 is a critical aspect of the mechanism responsible for altering inflammation, proliferation, and apoptosis [20][21][22][23][24][25][26][27].…”

“…APC increases proliferation and migration in keratinocytes by increasing the expression and activation of matrix metalloprotease-2 (MMP-2) [27]. Further, using a rat wound healing model, APC treatment reduced neutrophil infiltration and increased angiogenesis through MMP activation [28]. The initial studies looking at APC and cancer cell migration used ovarian cancer and choriocarcinoma cells in a transwell invasion assay [29].…”