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Cited by 257Blood Coagulation and Thrombosis MechanismsProtease and Inhibitor MechanismsComplement system in diseases

Activated protein C: biased for translation

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Griffin, John H., Zlokovic, Berislav V., Mosnier, Laurent O.·2015·Blood
DOI 10.1182/blood-2015-02-355974PMC PMC4424414
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Abstract

The homeostatic blood protease, activated protein C (APC), can function as (1) an antithrombotic on the basis of inactivation of clotting factors Va and VIIIa; (2) a cytoprotective on the basis of endothelial barrier stabilization and anti-inflammatory and antiapoptotic actions; and (3) a regenerative on the basis of stimulation of neurogenesis, angiogenesis, and wound healing. Pharmacologic therapies using recombinant human and murine APCs indicate that APC provides effective acute or chronic therapies for a strikingly diverse range of preclinical injury models. APC reduces the damage caused by the following: ischemia/reperfusion in brain, heart, and kidney; pulmonary, kidney, and gastrointestinal inflammation; sepsis; Ebola virus; diabetes; and total lethal body radiation. For these beneficial effects, APC alters cell signaling networks and gene expression profiles by activating protease-activated receptors 1 and 3. APC’s activation of these G protein–coupled receptors differs completely from thrombin’s activation mechanism due to biased signaling via either G proteins or β-arrestin-2. To reduce APC-associated bleeding risk, APC variants were engineered to lack >90% anticoagulant activity but retain normal cell signaling. Such a neuroprotective variant, 3K3A-APC (Lys191-193Ala), has advanced to clinical trials for ischemic stroke. A rich data set of preclinical knowledge provides a solid foundation for potential translation of APC variants to future novel therapies.

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  • Activated protein C cleaves protease-activated receptor 1 in brain endothelium and subsequently activates a beta-arrestin-2-dependent biased signaling pathway, which targets phosphatidylinositol 3-kinase for cytoprotection and Rac1 GTPase for sealing the blood-brain barrier.

    “APC cleaves protease-activated receptor 1 (PAR1) in brain endothelium and subsequently activates 𝛃 -arrestin-2-dependent biased signaling pathway, which targets phosphatidylinositol 3-kinase (PI3K) for cytoprotection and Rac1 GTPase for sealing the BBB (217).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [217]

    In “APC: mechanisms for PAR1-mediated biased signaling” (page not provided), the paper says APC cleavage of PAR1 initiates β-arrestin-2, PI3K/Akt, and Rac1 signaling, and that APC has endothelial barrier-protective effects. It does not specifically assign cytoprotection to PI3K and blood–brain barrier sealing to Rac1 in brain endothelium. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • A few pharmacological agents have been reported to restore blood-brain barrier function in animal models of acute neurological disorders and neurodegeneration.

    “Afewpharmacological agents have been reported to restore BBB function in animal models of acute neurological disorders (217, 697) and neurodegeneration (420).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [217]

    The ‘Preclinical studies of neuroprotective activity’ section reports that activated protein C reduced brain bleeding in murine stroke models, and ‘APC variants: preclinical studies’ reports benefits in models of stroke, traumatic brain injury, and ALS. Those passages support pharmacological benefits in acute neurological and neurodegenerative animal models, but they do not establish that treatment restored blood-brain barrier function. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Activated protein C exerts pleiotropic beneficial activities including protection of blood-brain barrier integrity, anti-inflammatory effects, direct neuroprotection, and pro-neurogenic and pro-angiogenic effects in rodent models of stroke, traumatic brain injury, and amyotrophic lateral sclerosis.

    “APC, for example, exerts pleotropic beneficial activities including protection of the BBB integrity, anti-inflammatory effects, direct neuroprotection, and pro-neurogenic and pro-angiogenic effects, as shown in rodent models of stroke, TBI, and ALS (217).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [217]

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References 121 · Cited by 257

Research works printed but not linked: 96

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Authors
Griffin, J. H., Zlokovic, B. V., & Mosnier, L. O.
Affiliations
  • Scripps Research Institute (US)
  • Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2015-05-07
Volume
125
Issue
19
Pages
2898-2907
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2015-02-355974
PMC
PMC4424414
OpenAlex
W2092338209
Cited by
257
References
121
Citations by year
2026: 9 · 2025: 20 · 2024: 19 · 2023: 26 · 2022: 19 · 2021: 24 · 2020: 31 · 2019: 17 · 2018: 28 · 2017: 28 · 2016: 24 · 2015: 12
FWCI
4.59
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (HL031950 and HL052246, HL031950, HL052246, HL063290)
  • National Heart, Lung, and Blood Institute (HL031950, R01HL063290, R01HL104165, HL052246, R01HL052246, HL063290, P01HL031950, HL104165, R37HL052246)
Topics
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
Keywords
activated protein C, biased signaling, protease-activated receptor 1, protease-activated receptor 3, β-arrestin2, thrombin, antithrombotic activity, factor Va inactivation, factor VIIIa inactivation, endothelial barrier, anti-inflammatory activity, anti-apoptotic effects, neurogenesis, angiogenesis, wound healing, ischemia-reperfusion injury, sepsis, Ebola virus, diabetes mellitus, radiation injury, neuroprotection, ischemic stroke, gene expression profiling, signal transduction
MeSH terms
Animals, Anticoagulants, Humans, Protein C, Cytoprotection

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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