Mice with a severe deficiency in protein C display prothrombotic and proinflammatory phenotypes and compromised maternal reproductive capabilities

Lay, Angelina J.; Zhong, Liang; Rosen, Elliot D.; Castellino, Francis J.

doi:10.1172/jci24030

Cited by 64 publications

(52 citation statements)

References 49 publications

(46 reference statements)

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“…To study the consequences of the decreased expression of epithelial PC in the inflamed intestine, we evaluated the susceptibility to experimental colitis in PC-deficient mice. Given that the genetic deletion of PC leads to death soon after birth, we used PC −/− /PC(Tg) ("low-PC") mice, which express only 3% of the amount of PC expressed by WT mice (13,14). When mice (6-8 wk old) underwent colonoscopy, low-PC mice had an endoscopic colitis score indicating the presence of spontaneous colitis characterized by mucosal hyperemia and friability (P < 0.05) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Vetrano

Ploplis

Sala

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The protein C (PC) pathway is a well-characterized coagulation system. Endothelial PC receptors and thrombomodulin mediate the conversion of PC to its activated form, a potent anticoagulant and anti-inflammatory molecule. Here we show that the PC pathway is expressed on intestinal epithelial cells. The epithelial expression of PC and endothelial PC receptor is down-regulated In patients with inflammatory bowel disease. PC −/− /PC(Tg) mice, expressing only 3% of WT PC, developed spontaneous intestinal inflammation and were prone to severe experimental colitis. These mice also demonstrated spontaneous elevated production of inflammatory cytokines and increased intestinal permeability. Structural analysis of epithelial tight junction molecules revealed that lack of PC leads to decreased JAM-A and claudin-3 expression and an altered pattern of ZO-1 expression. In vitro, treatment of epithelial cells with activated PC led to protection of tight junction disruption induced by TNF-α, and in vivo, topical treatment with activated PC led to mucosal healing and amelioration of colitis. Taken together, these findings demonstrate that the PC pathway is a unique system involved in controlling intestinal homeostasis and inflammation by regulating epithelial barrier function.

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Section: Resultsmentioning

confidence: 99%

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Vetrano

Ploplis

Sala

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Spontaneously, thrombotic PS-deficient murine phenotypes mimicking the human situation may likely require the generation of mice with more severe PS deficiency, as reported for protein C-deficient mice. 36 To characterize such mice with more severe PS deficiency, quantitation of PS levels by enzyme-linked immunosorbent assay or related methods will be needed, as to date no assay for normal PS plasma levels in mice has been reported in the literature. 37 This is mainly due to the lack of a sensitive and specific immunoassay, as has been developed for detecting mouse plasma APC.…”

Section: Discussionmentioning

confidence: 99%

Generation and phenotypic analysis of protein S–deficient mice

Saller

Brisset

Tchaikovski

et al. 2009

Blood

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Protein S (PS) is an important natural anticoagulant with potentially multiple biologic functions. To investigate further the role of PS in vivo, we generated Pros ؉/؊ heterozygous mice. In the null (؊) allele, the Pros exons 3 to 7 have been excised through conditional gene targeting. Pros ؉/؊ mice did not present any signs of spontaneous thrombosis and had reduced PS plasma levels and activated protein C cofactor activity in plasma coagulation and thrombin generation assays. Tissue factor pathway inhibitor cofactor activity of PS could not be demonstrated. Heterozygous Pros ؉/؊ mice exhibited a notable thrombotic phenotype in vivo when challenged in a tissue factor-induced thromboembolism model. No viable Pros ؊/؊ mice were obtained through mating of Pros ؉/؊ parents. Most E17.5 Pros ؊/؊ embryos were found dead with severe intracranial hemorrhages and most likely presented consumptive coagulopathy, as demonstrated by intravascular and interstitial fibrin deposition and an increased number of megakaryocytes in the liver, suggesting peripheral thrombocytopenia. A few E17.5 Pros ؊/؊ embryos had less severe phenotype, indicating that life-threatening manifestations might occur between E17.5 and the full term. Thus, similar to human phenotypes, mild heterozygous PS deficiency in mice was associated with a thrombotic phenotype, whereas total homozygous deficiency in PS was incompatible with life.

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“…11 Subsequently, targeted deletion of the murine protein C gene was found to cause perinatal lethality with pathological lesions in the brain. 12,13 Thus, both human and murine data prove protein C's essential physiological roles as an antithrombotic and anti-inflammatory protein.…”

Section: Introductionmentioning

confidence: 99%

Activated protein C: biased for translation

Griffin

Zloković

Mosnier

2015

Blood

221

320

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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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Mice with a severe deficiency in protein C display prothrombotic and proinflammatory phenotypes and compromised maternal reproductive capabilities

Cited by 64 publications

References 49 publications

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Generation and phenotypic analysis of protein S–deficient mice

Activated protein C: biased for translation

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