Activated protein C based therapeutic strategies in chronic diseases

Fabian Bock; Khurrum Shahzad; Nathalie Vergnolle; Berend Isermann

doi:10.1160/TH13-11-0967

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 111(04): 610-617
DOI: 10.1160/TH13-11-0967

Theme Issue Article

Schattauer GmbH

Activated protein C based therapeutic strategies in chronic diseases

Fabian Bock

¹Department of Clinical Chemistry and Pathobiochemistry, Magdeburg, Germany

²Department of Internal Medicine I and Clinical Chemistry, University of Heidelberg, INF 410, Heidelberg, Germany

,

Khurrum Shahzad

¹Department of Clinical Chemistry and Pathobiochemistry, Magdeburg, Germany

³University of Health Sciences, Khayaban-e-Jamia Punjab, Lahore, Pakistan

,

Nathalie Vergnolle

⁴Université Paul Sabatier, Centre de Physiopathologie de Toulouse, Institut National de la Santé et de la Recherche Médicale U1043, Toulouse, France

,

Berend Isermann

¹Department of Clinical Chemistry and Pathobiochemistry, Magdeburg, Germany

› Author Affiliations

Abstract

Summary

Activated protein C (aPC) is a natural anticoagulant and a potent antiinflammatory and cytoprotective agent. At the expense of increased bleeding risk aPC has been used – with some success – in sepsis. The design of cytoprotective-selective aPC variants circumvents this limitation of increased bleeding, reviving the interest in aPC as a therapeutic agent. Emerging studies suggest that aPC’s beneficial effects are not restricted to acute illness, but likewise relevant in chronic diseases, such as diabetic nephropathy, neurodegeneration or wound healing. Epigenetic regulation of gene expression, reduction of oxidative stress, and regulation of ROS-dependent transcription factors are potential mechanisms of sustained cytoprotective effects of aPC in chronic diseases. Given the available data it seems questionable whether a unifying mechanism of aPC dependent cytoprotection in acute and chronic diseases exists. In addition, the signalling pathways employed by aPC are tissue and cell specific. The mechanistic insights gained from studies exploring aPC’s effects in various diseases may hence lay ground for tissue and disease specific therapeutic approaches. This review outlines recent investigations into the mechanisms and consequences of long-term modulation of aPC-signalling in models of chronic diseases.

Keywords

Signal transduction - protein C/S pathway - diabetes mellitus - coagulation factors - chronic diseases

Full Text

References

References
1 Esmon CT. The protein C pathway.. Chest 2003; 124 (Suppl. 03) 26S-32S.
2 Stearns-Kurosawa DJ, Kurosawa S, Mollica JS. et al. The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex.. Proc Natl Acad Sci USA 1996; 93: 10212-10216.
3 Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway.. Blood 2007; 109: 3161-3172.
4 Schouten M, van’t Veer C, Roelofs JJ. et al. Recombinant activated protein C attenuates coagulopathy and inflammation when administered early in murine pneumococcal pneumonia.. Thromb Haemost 2011; 106: 1189-1196.
5 Schouten M, van’t Veer C, van den Boogaard FE. et al. Therapeutic recombi-nant murine activated protein C attenuates pulmonary coagulopathy and improves survival in murine pneumococcal pneumonia.. J Infect Dis 2010; 202: 1600-1607.
6 Liaw PC, Esmon CT, Kahnamoui K. et al. Patients with severe sepsis vary markedly in their ability to generate activated protein C.. Blood 2004; 104: 3958-3964.
7 Bernard GR, Vincent JL, Laterre PF. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis.. N Engl J Med 2001; 344: 699-709.
8 Ranieri VM, Thompson BT, Barie PS. et al. Drotrecogin alfa (activated) in adults with septic shock.. N Engl J Med 2012; 366: 2055-2064.
9 Marti-Carvajal AJ, Sola I, Lathyris D. et al. Human recombinant activated protein C for severe sepsis.. Cochrane Datab System Rev 2012; 3: CD004388.
10 Kerschen EJ, Fernandez JA, Cooley BC. et al. Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C.. J Exp Med 2007; 204: 2439-2448.
11 Griffin JH, Zlokovic BV, Mosnier LO. Protein C anticoagulant and cytoprotec-tive pathways.. Int J Hematol 2012; 95: 333-345.
12 Robson SC, White NW, Aronson I. et al. Acute-phase response and the hyperco-agulable state in pulmonary tuberculosis.. Br J Haematol 1996; 93: 943-949.
13 Turken O, Kunter E, Sezer M. et al. Hemostatic changes in active pulmonary tuberculosis.. Int J Tubercul Lung Dis 2002; 6: 927-932.
14 Oka S, Gabazza EC, Taguchi Y. et al. Role of activated protein C in Helicobacter pylori-associated gastritis.. Infect Immun 2000; 68: 2863-2869.
15 Weijer S, Wieland CW, Florquin S. et al. A thrombomodulin mutation that impairs activated protein C generation results in uncontrolled lung inflammation during murine tuberculosis.. Blood 2005; 106: 2761-2768.
16 Kager LM, Roelofs JJ, de Vos AF. et al. The endothelial protein C receptor and activated protein C play a limited role in host defense during experimental tuberculosis.. Thromb Haemost 2013; 109: 726-737.
17 Cakal B, Gokmen A, Yalinkilic M. et al. Natural anticoagulant protein levels in Turkish patients with inflammatory bowel disease.. Blood Coagul Fibrinol 2010; 21: 118-121.
18 De Cristofaro R, Rocca B, Vitacolonna E. et al. Lipid and protein oxidation contribute to a prothrombotic state in patients with type 2 diabetes mellitus.. J Thromb Haemost 2003; 1: 250-256.
19 Mezzano D, Espana F, Panes O. et al. Increased activation of protein C, but lower plasma levels of free, activated protein C in uraemic patients: relationship with systemic inflammation and haemostatic activation.. Br J Haematol 2001; 113: 905-910.
20 Nampoory MR, Das KC, Johny KV. et al. Hypercoagulability, a serious problem in patients with ESRD on maintenance hemodialysis, and its correction after kidney transplantation.. Am J Kidney Dis 2003; 42: 797-805.
21 Zorio E, Navarro S, Medina P. et al. Circulating activated protein C is reduced in young survivors of myocardial infarction and inversely correlates with the severity of coronary lesions.. J Thromb Haemost 2006; 4: 1530-1536.
22 Whitmont K, Fulcher G, Reid I. et al. Low circulating protein C levels are associated with lower leg ulcers in patients with diabetes.. BioMed Res Intern 2013; 2013: 719570.
23 Matsumoto K, Yano Y, Gabazza EC. et al. Inverse correlation between activated protein C generation and carotid atherosclerosis in Type 2 diabetic patients.. Diabetic Med 2007; 24: 1322-1328.
24 Adams MN, Ramachandran R, Yau MK. et al. Structure, function and pathophysiology of protease activated receptors.. Pharmacol Therap 2011; 130: 248-282.
25 Bock F, Shahzad K, Wang H. et al. Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc.. Proc Natl Acad Sci USA 2013; 110: 648-653.
26 Zhong Z, Ilieva H, Hallagan L. et al. Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells.. J Clin Invest 2009; 119: 3437-3449.
27 Mosnier LO, Gale AJ, Yegneswaran S. et al. Activated protein C variants with normal cytoprotective but reduced anticoagulant activity.. Blood 2004; 104: 1740-1744.
28 Mosnier LO, Yang XV, Griffin JH. Activated protein C mutant with minimal anticoagulant activity, normal cytoprotective activity, and preservation of thrombin activable fibrinolysis inhibitor-dependent cytoprotective functions.. J Biol Chem 2007; 282: 33022-33033.
29 Zlokovic BV, Griffin JH. Cytoprotective protein C pathways and implications for stroke and neurological disorders.. Trends Neurosci 2011; 34: 198-209.
30 Gupta A, Gerlitz B, Richardson MA. et al. Distinct functions of activated protein C differentially attenuate acute kidney injury.. J Am Soc Nephrol 2009; 20: 267-277.
31 Bae JS, Yang L, Manithody C. et al. Engineering a disulfide bond to stabilize the calcium-binding loop of activated protein C eliminates its anticoagulant but not its protective signalling properties.. J Biol Chem 2007; 282: 9251-9259.
32 Kerschen E, Hernandez I, Zogg M. et al. Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice.. J Clin Invest 2010; 120: 3167-3178.
33 Williams PD, Zlokovic BV, Griffin JH. et al. Preclinical safety and pharmacokinetic profile of 3K3A-APC, a novel, modified activated protein C for ischemic stroke.. Curr Pharm Design 2012; 18: 4215-4222.
34 Lyden P, Levy H, Weymer S. et al. Phase 1 safety, tolerability and pharmacoki-netics of 3K3A-APC in healthy adult volunteers.. Curr Pharm Design 2013; 19: 7479-7485.
35 Park SW, Chen SW, Kim M. et al. Human activated protein C attenuates both hepatic and renal injury caused by hepatic ischemia and reperfusion injury in mice.. Kidney Int 2009; 76: 739-750.
36 Gupta A, Rhodes GJ, Berg DT. et al. Activated protein C ameliorates LPS-in-duced acute kidney injury and downregulates renal INOS and angiotensin 2.. Am J Physiol Renal Physiol 2007; 293: F245-254.
37 Hofmann MA, Kohl B, Zumbach MS. et al. Hyperhomocyst(e)inemia and endothelial dysfunction in IDDM.. Diabetes Care 1998; 21: 841-848.
38 Isermann B, Vinnikov IA, Madhusudhan T. et al. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis.. Nature Med 2007; 13: 1349-1358.
39 Weiler-Guettler H, Christie PD, Beeler DL. et al. A targeted point mutation in thrombomodulin generates viable mice with a prethrombotic state.. J Clin Invest 1998; 101: 1983-1991.
40 Gil-Bernabe P, D’Alessandro-Gabazza CN, Toda M. et al. Exogenous activated protein C inhibits the progression of diabetic nephropathy.. J Thromb Haemost 2012; 10: 337-346.
41 Aird WC. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms.. Circ Res 2007; 100: 158-173.
42 Yamaji K, Wang Y, Liu Y. et al. Activated protein C, a natural anticoagulant protein, has antioxidant properties and inhibits lipid peroxidation and advanced glycation end products formation.. Thromb Res 2005; 115: 319-325.
43 Sennoun N, Meziani F, Dessebe O. et al. Activated protein C improves lipopoly-saccharide-induced cardiovascular dysfunction by decreasing tissular inflammation and oxidative stress.. Crit Care Med 2009; 37: 246-255.
44 Madhusudhan T, Wang H, Straub BK. et al. Cytoprotective signalling by activated protein C requires protease-activated receptor-3 in podocytes.. Blood 2012; 119: 874-883.
45 Burnier L, Mosnier LO. Novel mechanisms for activated protein C cytoprotec-tive activities involving noncanonical activation of protease-activated receptor 3.. Blood 2013; 122: 807-816.
46 Soh UJ, Dores MR, Chen B. et al. Signal transduction by protease-activated receptors.. Br J Pharmacol 2010; 160: 191-203.
47 Hollenberg MD, Compton SJ. International Union of Pharmacology. XXVIII. Proteinase-activated receptors.. Pharmacol Rev 2002; 54: 203-217.
48 Laszik Z, Mitro A, Taylor Jr. FB. et al. Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway.. Circulation 1997; 96: 3633-3640.
49 Crawley JT, Gu JM, Ferrell G. et al. Distribution of endothelial cell protein C/ac-tivated protein C receptor (EPCR) during mouse embryo development.. Thromb Haemost 2002; 88: 259-266.
50 Han MH, Hwang SI, Roy DB. et al. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets.. Nature 2008; 451: 1076-1081.
51 Xue M, Dervish S, Harrison LC. et al. Activated protein C inhibits pancreatic islet inflammation, stimulates T regulatory cells, and prevents diabetes in non-obese diabetic (NOD) mice.. J Biol Chem 2012; 287: 16356-16364.
52 Zushi M, Gomi K, Yamamoto S. et al. The last three consecutive epidermal growth factor-like structures of human thrombomodulin comprise the minimum functional domain for protein C-activating cofactor activity and anticoagulant activity.. J Biol Chem 1989; 264: 10351-10353.
53 Wang H, Vinnikov I, Shahzad K. et al. The lectin-like domain of thrombomodu-lin ameliorates diabetic glomerulopathy via complement inhibition.. Thromb Haemost 2012; 108: 1141-1153.
54 Conway EM, Van de Wouwer M, Pollefeyt S. et al. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mi-togen-activated protein kinase pathways.. J Exp Med 2002; 196: 565-577.
55 Deane R, LaRue B, Sagare AP. et al. Endothelial protein C receptor-assisted transport of activated protein C across the mouse blood-brain barrier.. J Cereb Blood Flow Metabol 2009; 29: 25-33.
56 Boillee S, Vande Velde C, Cleveland DW. ALS: a disease of motor neurons and their nonneuronal neighbors.. Neuron 2006; 52: 39-59.
57 Alabanza LM, Esmon NL, Esmon CT. et al. Inhibition of endogenous activated protein C attenuates experimental autoimmune encephalomyelitis by inducing myeloid-derived suppressor cells.. J Immunol 2013; 191: 3764-3777.
58 Kaneider NC, Leger AJ, Agarwal A. et al. ‘Role reversal’ for the receptor PAR1 in sepsis-induced vascular damage.. Nature Immunol 2007; 8: 1303-1312.
59 Shahzad K, Isermann B. The evolving plasticity of coagulation protease-de-pendent cytoprotective signalling.. Hämostaseol 2011; 31: 179-184.
60 Spek CA, Arruda VR. The protein C pathway in cancer metastasis.. Thromb Res 2012; 129 (Suppl. 01) S80-84.
61 Julovi SM, Xue M, Dervish S. et al. Protease activated receptor-2 mediates activated protein C-induced cutaneous wound healing via inhibition of p38.. Am J Pathol 2011; 179: 2233-2242.
62 Belting M, Dorrell MI, Sandgren S. et al. Regulation of angiogenesis by tissue factor cytoplasmic domain signalling.. Nature Med 2004; 10: 502-509.
63 Jackson CJ, Xue M, Thompson P. et al. Activated protein C prevents inflammation yet stimulates angiogenesis to promote cutaneous wound healing.. Wound Repair Regen 2005; 13: 284-294.
64 Uchiba M, Okajima K, Oike Y. et al. Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo.. Circ Res 2004; 95: 34-41.
65 Xue M, Campbell D, Sambrook PN. et al. Endothelial protein C receptor and protease-activated receptor-1 mediate induction of a wound-healing phenotype in human keratinocytes by activated protein C.. J Invest Dermatol 2005; 125: 1279-1285.
66 Xue M, Chow SO, Dervish S. et al. Activated protein C enhances human kerati-nocyte barrier integrity via sequential activation of epidermal growth factor receptor and Tie2.. J Biol Chem 2011; 286: 6742-6750.
67 Xue M, Thompson P, Sambrook PN. et al. Activated protein C stimulates expression of angiogenic factors in human skin cells, angiogenesis in the chick embryo and cutaneous wound healing in rodents.. Clin Haemorheol Microcirc 2006; 34: 153-161.
68 Whitmont K, Reid I, Tritton S. et al. Treatment of chronic leg ulcers with topical activated protein C.. Arch Dermatol 2008; 144: 1479-1483.
69 Wijewardena A, Vandervord E, Lajevardi SS. et al. Combination of activated protein C and topical negative pressure rapidly regenerates granulation tissue over exposed bone to heal recalcitrant orthopedic wounds.. Intern J Low Extrem Wounds 2011; 10: 146-151.
70 Whitmont K, McKelvey KJ, Fulcher G. et al. Treatment of chronic diabetic lower leg ulcers with activated protein C: a randomised placebo-controlled, doubleblind pilot clinical trial.. Intern Wound J. 2013 Epub ahead of print.
71 Vetrano S, Ploplis VA, Sala E. et al. Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation.. Proc Natl Acad Sci USA 2011; 108: 19830-19835.
72 Furugohri T, Shiozaki Y, Muramatsu S. et al. Different antithrombotic properties of factor Xa inhibitor and thrombin inhibitor in rat thrombosis models.. Eur J Pharmacol 2005; 514: 35-42.
73 Furugohri T, Sugiyama N, Morishima Y. et al. Antithrombin-independent thrombin inhibitors, but not direct factor Xa inhibitors, enhance thrombin generation in plasma through inhibition of thrombin-thrombomodulin-protein C system.. Thromb Haemost 2011; 106: 1076-1083.
74 Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials.. Arch Intern Med 2012; 172: 397-402.
75 Vincent JL, Ramesh MK, Ernest D. A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation.. Crit Care Med 2013; 41: 2069-2079.