Protein C anticoagulant and cytoprotective pathways

Griffin, John H.; Zloković, Berislav V.; Mosnier, Laurent O.

doi:10.1007/s12185-012-1059-0

Cited by 121 publications

(95 citation statements)

References 173 publications

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“…I t is well established that coagulation proteases have functions extending well beyond the regulation of intravascular hemostasis (1). In addition to their role in hemostasis, some coagulation proteases, such as thrombin and activated protein C (aPC), have important functions in regulating cellular homeostasis.…”

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confidence: 99%

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Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 ^Shc

Bock

Shahzad

Wang

et al. 2012

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

131

178

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The coagulation protease activated protein C (aPC) confers cytoprotective effects in various in vitro and in vivo disease models, including diabetic nephropathy. The nephroprotective effect may be related to antioxidant effects of aPC. However, the mechanism through which aPC may convey these antioxidant effects and the functional relevance of these properties remain unknown. Here, we show that endogenous and exogenous aPC prevents glomerular accumulation of oxidative stress markers and of the redox-regulating protein p66 Shc in experimental diabetic nephropathy. These effects were predominately observed in podocytes. In vitro, aPC inhibited glucose-induced expression of p66 Shc mRNA and protein in podocytes (via PAR-1 and PAR-3) and various endothelial cell lines, but not in glomerular endothelial cells. Treatment with aPC reversed glucose-induced hypomethylation and hyperacetylation of the p66 Shc promoter in podocytes. The hyperacetylating agent sodium butyrate abolished the suppressive effect of aPC on p66 Shc expression both in vitro and in vivo. Moreover, sodium butyrate abolished the beneficial effects of aPC in experimental diabetic nephropathy. Inhibition of p66 Shc expression and mitochondrial translocation by aPC normalized mitochondrial ROS production and the mitochondrial membrane potential in glucose-treated podocytes. Genetic ablation of p66 Shc compensated for the loss of protein C activation in vivo, normalizing markers of diabetic nephropathy and oxidative stress. These studies identify a unique mechanism underlying the cytoprotective effect of aPC. Activated PC epigenetically controls expression of the redox-regulating protein p66 Shc , thus linking the extracellular protease aPC to mitochondrial function in diabetic nephropathy.

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confidence: 99%

“…aPC mediates its anticoagulant effects by inactivating the coagulation cofactors Va and VIIIa. In addition, aPC confers a number of cytoprotective effects, which are largely independent of its anticoagulant function and depend on the regulation of intracellular signaling pathways through receptordependent mechanisms (1).…”

mentioning

confidence: 99%

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 ^Shc

Bock

Shahzad

Wang

et al. 2012

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

131

178

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“…APC binding regions of PS are located in the TSR, EGF‐1, and EGF‐2 domains 2. Based on modeling of the tertiary structure of the EGF‐2 domain of PS, Lys 196 is on the surface of the molecule,4 where it likely interacts with APC. The functional importance of Lys 196 was previously reported by an Ala replacement study, where the K196A variant showed modestly reduced APC cofactor activity 22.…”

Section: Resultsmentioning

confidence: 99%

Protein S K196E mutation reduces its cofactor activity for APC but not for TFPI

Maruyama

Akiyama

Miyata

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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BackgroundProtein S (PS) is an anticoagulant molecule that functions as a cofactor for activated protein C (APC) in the inactivation of activated coagulation factors Va (FVa) and VIIIa. It also serves as a cofactor for tissue factor pathway inhibitor (TFPI) in the efficient inhibition of factor Xa (FXa). The Lys196‐to‐Glu (K196E, Tokushima) mutation in the EGF‐2 domain of PS is a genetic risk factor for venous thromboembolism (VTE) in the Japanese population.ObjectivesTo investigate the molecular basis of the thrombophilic phenotype of Japanese patients carrying the PS K196E mutation.MethodsWe expressed recombinant human PS wild‐type (PS‐K) and K196E‐mutant (PS‐E) in CHO cells, and purified them by Ni2+‐affinity and anion exchange column chromatography. We investigated the anticoagulant functions of PS‐K and PS‐E by measuring APC cofactor activity, TFPI cofactor activity, affinity for the β chain of complement component C4b‐binding protein (C4BP), and cleavage by thrombin.Results PS‐E had approximately 40% APC cofactor activity compared with PS‐K in a clotting‐based assay and a FVa inactivation assay. The TFPI cofactor activity of PS‐E in the FXa inactivation assay was equivalent to that of PS‐K in the absence and presence of coagulation factor V. The strengths of PS‐E and PS‐K binding to the β chain of C4BP were comparable, and both were equally cleaved by thrombin.ConclusionsThe PS K196E mutation increases the risk of VTE because of reduced APC cofactor activity but does not alter various other properties, including the TFPI cofactor activity.

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“…Proteins C and S (PC and PS) are vitamin K-dependent plasma glycoproteins that exert their anticoagulant actions through the degradation of clotting factors VIIIa and Va. After activation by the thrombin-thrombomodulin complex, activated protein C (APC) acts as a specific protease with PS acting as a non-enzymatic cofactor [1,2]. The human gene encoding PC (PROC) is located on the long arm of chromosome 2 (2q13-q14) and contains 9 exons that code for 461 amino acid residues [3,4].…”

Section: Introductionmentioning

confidence: 99%

“…Hereditary deficiencies of either PC or PS are rare autosomal dominant disorders in which patients have functional levels of the respective proteins that are typically half those of normal controls, resulting in increased propensity toward thromboembolic disease [2,8,9]. Like other inherited hemostatic disorders, deficiencies of PC or PS are the result of heterogeneous deletions and mutations that affect protein secretion, stability and/or function.…”

Section: Introductionmentioning

confidence: 99%

Identification of two novel mutations associated with combined protein C and protein S deficiency

Smith¹,

Carter²,

Smith³

et al. 2017

Vascul Dis Ther

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We have studied a 60 year old male of Chinese descent who presented with combined deficiency of the anticoagulant proteins C and S. Molecular genetic analysis of the patient's PROC gene revealed a novel heterozygous mutation that resulted in a V221G mutation. Two mutations were identified in the patient's PROS1 gene:(1) an E67E mutation that has been reported previously and is associated with severe protein S deficiency, and (2) a novel mutation in the 5' flanking sequence that changes a putative binding site for the transcription factor Sp 1. Together, these mutations are consistent with the combined protein C and S deficiency symptoms presented by the patient.

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Protein C anticoagulant and cytoprotective pathways

Cited by 121 publications

References 173 publications

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 ^Shc

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 ^Shc

Protein S K196E mutation reduces its cofactor activity for APC but not for TFPI

Identification of two novel mutations associated with combined protein C and protein S deficiency

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Protein C anticoagulant and cytoprotective pathways

Cited by 121 publications

References 173 publications

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 Shc

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 Shc

Protein S K196E mutation reduces its cofactor activity for APC but not for TFPI

Identification of two novel mutations associated with combined protein C and protein S deficiency

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Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 ^Shc

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 ^Shc