Activated Protein C in Cutaneous Wound Healing: From Bench to Bedside

Abstract

Independent of its well-known anticoagulation effects, activated protein C (APC) exhibits pleiotropic cytoprotective properties. These include anti-inflammatory actions, anti-apoptosis, and endothelial and epithelial barrier stabilisation. Such beneficial effects have made APC an attractive target of research in a plethora of physiological and pathophysiological processes. Of note, the past decade or so has seen the emergence of its roles in cutaneous wound healing—a complex process involving inflammation, proliferation and remodelling. This review will highlight APC’s functions and mechanisms, and detail its pre-clinical and clinical studies on cutaneous wound healing.

Activated Protein C (APC) and 3K3A-APC-Induced Regression of Choroidal Neovascularization (CNV) Is Accompanied by Vascular Endothelial Growth Factor (VEGF) Reduction

“…The ability of APC to reduce VEGF expression and to oppose VEGF-induced endothelial permeability was previously demonstrated in-vivo in a skin model [34] and a diabetic nephropathy mouse model [35]. In contrast, an elevation in VEGF levels and a proangiogenic effect of APC were demonstrated in other pathological models [36][37][38][39][40]. The angiogenic process' complexity and the variability between vascular beds may modify the balance between pro-angiogenic and anti-angiogenic effects.…”

“…Disruption of the outer BRB is a crucial step in the pathogenesis of CNV [1]. Barrier stabilizing properties, including the RPE barrier tightening induced by APC [4,7,18,34,40], may contribute to CNV suppression. By stabilizing the RPE barrier integrity, APC may restrict choroidal endothelial cell migration through the RPE and limit CNV invasion into the sensory retina.…”

Severe Protein C Deficiency due to Novel Biallelic Variants in <b><i>PROC</i></b> and Their Phenotype Correlation

“…Our patients displayed severe recurrent PF yielding permanent mild scaring in 2 out of 3, while 1 patient required plastic surgery. Human epidermal keratinocytes express PC and APC promotes proliferation in cultured human keratinocytes [12]. As cutaneous wound healing is a complex process involving inflammation, proliferation, and remodeling, congenital SPCD is always associated with PF.…”

The Cardioprotective Signaling Activity of Activated Protein C in Heart Failure and Ischemic Heart Diseases

“…In addition to its cardioprotective properties, APC exhibits potent cytoprotective and anti-inflammatory effects in a number of other acute and chronic diseases including sepsis [94], ischemic stroke [95], acute kidney injury [96], type-1 diabetes [97], wound healing [98], Plasmodium falciparum malaria [99], post-surgical adhesion band formation [100] and other inflammatory disorders that have been nicely reviewed in recent review articles [101,102]. There are several ongoing pre-clinical and clinical trials evaluating the potential therapeutic utility of APC in animals and humans [101,102]. The future studies with the signaling-selective APC derivatives which do not exhibit significant anticoagulant activities and thus are not associated with an increased risk of bleeding may provide APC-based therapeutic strategies for some of these inflammatory diseases.…”