Download PDF
Hamostaseologie 2019; 39(02): 164-172
DOI: 10.1055/s-0039-1688800
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Coagulation Signalling and Metabolic Disorders: Lessons Learned from Animal Models

Thati Madhusudhan
1   Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
,
Wolfram Ruf
1   Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
2   Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States
3   German Center for Cardiovascular Research (DZHK), Partner site Rhein-Main, Berlin-Wedding, Germany
› Author Affiliations
Further Information

Publication History

04 July 2018

04 April 2019

Publication Date:
27 May 2019 (online)

Also available at
    Permissions and Reprints

Abstract

Nutrient excess in obesity drives metabolic reprogramming in multiple tissues involving extensive interorgan and intercellular crosstalk. Experimental and clinical studies show that prolonged nutrient excess often compromises metabolic adaptation propagating proobesogenic and proinflammatory responses. Chronic inflammation further promotes insulin resistance and associated comorbidities. Obesity and type 2 diabetes are characterized by a hypercoagulable state and clinical studies show a strong correlation of markers of coagulation activation in metabolic disorders. Coagulation protease-dependent signalling via protease-activated receptors is intimately associated with inflammation. The experimental evidence supports roles of tissue factor and G protein coupled protease-activated receptor-2 signalling in the regulation of insulin resistance and metabolic inflammation in diet-induced obesity. Likewise, increases in plasminogen activator inhibitor-1 levels and fibrin-driven inflammation promote insulin resistance in obesity. Additionally, impaired thrombomodulin-dependent protein C activation is mechanistically linked to diabetic kidney disease. Given the increased usage of direct oral anticoagulants, understanding the role of specific coagulation proteases in regulation of metabolic inflammation is highly relevant and might provide insights into the design of novel treatment regimens for patients suffering from thromboinflammatory and cardiometabolic disorders.

Zusammenfassung

Durch Nährstoffüberschuss ausgelöste Adipositas führt zur Veränderung von metabolischen Prozessen in einer Vielzahl von Geweben mit der Konsequenz von komplexen pathologischen Wechselwirkungen auf zellulärer Ebene. So zeigen experimentelle und klinische Studien, dass ein über längeren Zeitraum aufgenommener Nährstoffüberschuss adipogene und proinflammatorischen Reaktionen fördert und eine Anpassung des Stoffwechsels kompromittieren. Durch die Manifestierung chronisch entzündlicher Prozesse werden Insulinresistenz und damit verbundene Komorbiditäten verstärkt. Außerdem gehen Adipositas und Typ-2-Diabetes mit einer Hyperkoagulabilität einher. In klinische Studien konnte gezeigt werden, dass Gerinnungsaktivierungsmarker mit Stoffwechselstörungen korrelieren. Dabei vermitteln von der Gerinnungskaskade aktivierte Protease-aktivierte-Rezeptoren (PARs) entzündliche Prozesse. Es konnte experimentell gezeigt werden, dass das Gewebethromboplastin (tissue factor, TF) und die Signale des G Protein gekoppelten Rezeptors PAR2 an den pathologischen Regulationsprozessen in ernährungsbedingter Adipositas, wie die Insulinresistenz beteiligt sind. Ebenso werden Fettleibigkeit und Insulinresistenz durch einen Anstieg des Plasminogenaktivator-Inhibitor-1 und fibringesteuerte Entzündungen gefördert. Darüber hinaus ist die beeinträchtigte Thrombomodulin-abhängige Protein C Aktivierung mechanistisch mit einer diabetischen Nephrophathie verbunden. Angesichts des zunehmenden Einsatzes oraler Antikoagulantien benötigt es ein verbessertes Verständnis, wie spezifische Gerinnungsfaktoren entzündliche Prozesse in Stoffwechselerkrankungen regulieren. Dies könnte Einblicke geben, die zu neuartigen Behandlungsansätze für Patienten mit Gerinnung-Störungen und kardio-metabolischen Erkrankungen führen.

Keywords

coagulation proteases - metabolic diseases - protease-activated receptors

Schlüsselwörter

Gerinnungsproteasen - metabilsche Erkrankungen - Protease-aktivierte Rezeptoren
 

  • References

  • 1 Singer K, Lumeng CN. The initiation of metabolic inflammation in childhood obesity. J Clin Invest 2017; 127 (01) 65-73
    CrossrefPubMedGoogle Scholar
  • 2 Lu Y, Hajifathalian K, Ezzati M, Woodward M, Rimm EB, Danaei G. ; Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration (BMI Mediated Effects). Metabolic mediators of the effects of body-mass index, overweight, and obesity on coronary heart disease and stroke: a pooled analysis of 97 prospective cohorts with 1·8 million participants. Lancet 2014; 383 (9921): 970-983
    CrossrefPubMedGoogle Scholar
  • 3 Di Angelantonio E, Bhupathiraju ShN, Wormser D. , et al; Global BMI Mortality Collaboration. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet 2016; 388 (10046): 776-786
    CrossrefPubMedGoogle Scholar
  • 4 Ridker PM, Everett BM, Thuren T. , et al; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377 (12) 1119-1131
    CrossrefPubMedGoogle Scholar
  • 5 Goldfine AB, Shoelson SE. Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk. J Clin Invest 2017; 127 (01) 83-93
    CrossrefPubMedGoogle Scholar
  • 6 Badeanlou L, Furlan-Freguia C, Yang G, Ruf W, Samad F. Tissue factor-protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation. Nat Med 2011; 17 (11) 1490-1497
    CrossrefPubMedGoogle Scholar
  • 7 Anand SS, Bosch J, Eikelboom JW. , et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018; 391 (10117): 219-229
    CrossrefPubMedGoogle Scholar
  • 8 Samad F, Ruf W. Inflammation, obesity, and thrombosis. Blood 2013; 122 (20) 3415-3422
    PubMedGoogle Scholar
  • 9 Kagota S, Maruyama K, McGuire JJ. Characterization and functions of protease-activated receptor 2 in obesity, diabetes, and metabolic syndrome: a systematic review. BioMed Res Int 2016; 2016: 3130496
    PubMedGoogle Scholar
  • 10 Rothmeier AS, Ruf W. Protease-activated receptor 2 signaling in inflammation. Semin Immunopathol 2012; 34 (01) 133-149
    CrossrefPubMedGoogle Scholar
  • 11 Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost 2005; 3 (08) 1800-1814
    CrossrefPubMedGoogle Scholar
  • 12 Li M, Yang X, Zhang Y. , et al. Activation of protease‑activated receptor‑2 is associated with increased expression of inflammatory factors in the adipose tissues of obese mice. Mol Med Rep 2015; 12 (04) 6227-6234
    CrossrefPubMedGoogle Scholar
  • 13 De Pergola G, Pannacciulli N. Coagulation and fibrinolysis abnormalities in obesity. J Endocrinol Invest 2002; 25 (10) 899-904
    CrossrefPubMedGoogle Scholar
  • 14 Siklar Z, Öçal G, Berberoğlu M. , et al. Evaluation of hypercoagulability in obese children with thrombin generation test and microparticle release: effect of metabolic parameters. Clin Appl Thromb Hemost 2011; 17 (06) 585-589
    CrossrefPubMedGoogle Scholar
  • 15 Morange PE, Alessi MC. Thrombosis in central obesity and metabolic syndrome: mechanisms and epidemiology. Thromb Haemost 2013; 110 (04) 669-680
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Wang J, Ciaraldi TP, Samad F. Tissue factor expression in obese type 2 diabetic subjects and its regulation by antidiabetic agents. J Obes 2015; 2015: 291209
    PubMedGoogle Scholar
  • 17 Alessi MC, Juhan-Vague I. PAI-1 and the metabolic syndrome: links, causes, and consequences. Arterioscler Thromb Vasc Biol 2006; 26 (10) 2200-2207
    CrossrefPubMedGoogle Scholar
  • 18 Samad F, Yamamoto K, Loskutoff DJ. Distribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo. Induction by tumor necrosis factor-alpha and lipopolysaccharide. J Clin Invest 1996; 97 (01) 37-46
    CrossrefPubMedGoogle Scholar
  • 19 Kopp CW, Kopp HP, Steiner S. , et al. Weight loss reduces tissue factor in morbidly obese patients. Obes Res 2003; 11 (08) 950-956
    PubMedGoogle Scholar
  • 20 Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006; 444 (7121): 840-846
    CrossrefPubMedGoogle Scholar
  • 21 Klovaite J, Benn M, Nordestgaard BG. Obesity as a causal risk factor for deep venous thrombosis: a Mendelian randomization study. J Intern Med 2015; 277 (05) 573-584
    CrossrefPubMedGoogle Scholar
  • 22 Ayer JG, Song C, Steinbeck K, Celermajer DS, Ben Freedman S. Increased tissue factor activity in monocytes from obese young adults. Clin Exp Pharmacol Physiol 2010; 37 (11) 1049-1054
    CrossrefPubMedGoogle Scholar
  • 23 Tripodi A, Branchi A, Chantarangkul V. , et al. Hypercoagulability in patients with type 2 diabetes mellitus detected by a thrombin generation assay. J Thromb Thrombolysis 2011; 31 (02) 165-172
    CrossrefPubMedGoogle Scholar
  • 24 Boden G, Vaidyula VR, Homko C, Cheung P, Rao AK. Circulating tissue factor procoagulant activity and thrombin generation in patients with type 2 diabetes: effects of insulin and glucose. J Clin Endocrinol Metab 2007; 92 (11) 4352-4358
    CrossrefPubMedGoogle Scholar
  • 25 Diamant M, Nieuwland R, Pablo RF, Sturk A, Smit JW, Radder JK. Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus. Circulation 2002; 106 (19) 2442-2447
    CrossrefPubMedGoogle Scholar
  • 26 Gerrits AJ, Koekman CA, van Haeften TW, Akkerman JW. Increased tissue factor expression in diabetes mellitus type 2 monocytes caused by insulin resistance. J Thromb Haemost 2011; 9 (04) 873-875
    CrossrefPubMedGoogle Scholar
  • 27 Uchida Y, Takeshita K, Yamamoto K. , et al. Stress augments insulin resistance and prothrombotic state: role of visceral adipose-derived monocyte chemoattractant protein-1. Diabetes 2012; 61 (06) 1552-1561
    CrossrefPubMedGoogle Scholar
  • 28 Ruf W. Proteases, protease-activated receptors, and atherosclerosis. Arterioscler Thromb Vasc Biol 2018; 38 (06) 1252-1254
    CrossrefPubMedGoogle Scholar
  • 29 Madhusudhan T, Kerlin BA, Isermann B. The emerging role of coagulation proteases in kidney disease. Nat Rev Nephrol 2016; 12 (02) 94-109
    CrossrefPubMedGoogle Scholar
  • 30 Samad F, Loskutoff DJ. Tissue distribution and regulation of plasminogen activator inhibitor-1 in obese mice. Mol Med 1996; 2 (05) 568-582
    CrossrefPubMedGoogle Scholar
  • 31 Barnard SA, Pieters M, De Lange Z. The contribution of different adipose tissue depots to plasma plasminogen activator inhibitor-1 (PAI-1) levels. Blood Rev 2016; 30 (06) 421-429
    CrossrefPubMedGoogle Scholar
  • 32 Schäfer K, Fujisawa K, Konstantinides S, Loskutoff DJ. Disruption of the plasminogen activator inhibitor 1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice. FASEB J 2001; 15 (10) 1840-1842
    CrossrefPubMedGoogle Scholar
  • 33 Lijnen HR. Effect of plasminogen activator inhibitor-1 deficiency on nutritionally-induced obesity in mice. Thromb Haemost 2005; 93 (05) 816-819
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Guha M, Mackman N. LPS induction of gene expression in human monocytes. Cell Signal 2001; 13 (02) 85-94
    CrossrefPubMedGoogle Scholar
  • 35 Breitenstein A, Stein S, Holy EW. , et al. Sirt1 inhibition promotes in vivo arterial thrombosis and tissue factor expression in stimulated cells. Cardiovasc Res 2011; 89 (02) 464-472
    CrossrefPubMedGoogle Scholar
  • 36 Ruf W, Samad F. Tissue factor pathways linking obesity and inflammation. Hamostaseologie 2015; 35 (03) 279-283
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Wang J, Chakrabarty S, Bui Q, Ruf W, Samad F. Hematopoietic tissue factor-protease-activated receptor 2 signaling promotes hepatic inflammation and contributes to pathways of gluconeogenesis and steatosis in obese mice. Am J Pathol 2015; 185 (02) 524-535
    CrossrefPubMedGoogle Scholar
  • 38 Kopec AK, Abrahams SR, Thornton S. , et al. Thrombin promotes diet-induced obesity through fibrin-driven inflammation. J Clin Invest 2017; 127 (08) 3152-3166
    CrossrefPubMedGoogle Scholar
  • 39 Kassel KM, Owens III AP, Rockwell CE. , et al. Protease-activated receptor 1 and hematopoietic cell tissue factor are required for hepatic steatosis in mice fed a Western diet. Am J Pathol 2011; 179 (05) 2278-2289
    CrossrefPubMedGoogle Scholar
  • 40 Luyendyk JP, Sullivan BP, Guo GL, Wang R. Tissue factor-deficiency and protease activated receptor-1-deficiency reduce inflammation elicited by diet-induced steatohepatitis in mice. Am J Pathol 2010; 176 (01) 177-186
    CrossrefPubMedGoogle Scholar
  • 41 Nault R, Fader KA, Kopec AK, Harkema JR, Zacharewski TR, Luyendyk JP. From the cover: coagulation-driven hepatic fibrosis requires protease activated receptor-1 (PAR-1) in a mouse model of TCDD-elicited steatohepatitis. Toxicol Sci 2016; 154 (02) 381-391
    CrossrefPubMedGoogle Scholar
  • 42 Eikelboom JW, Connolly SJ, Bosch J. , et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377 (14) 1319-1330
    CrossrefPubMedGoogle Scholar
  • 43 Connolly SJ, Eikelboom JW, Bosch J. , et al. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018; 391 (10117): 205-218
    CrossrefPubMedGoogle Scholar
  • 44 Borissoff JI, Otten JJ, Heeneman S. , et al. Genetic and pharmacological modifications of thrombin formation in apolipoprotein e-deficient mice determine atherosclerosis severity and atherothrombosis onset in a neutrophil-dependent manner. PLoS One 2013; 8 (02) e55784
    CrossrefPubMedGoogle Scholar
  • 45 Eitzman DT, Westrick RJ, Shen Y. , et al. Homozygosity for factor V Leiden leads to enhanced thrombosis and atherosclerosis in mice. Circulation 2005; 111 (14) 1822-1825
    CrossrefPubMedGoogle Scholar
  • 46 Seehaus S, Shahzad K, Kashif M. , et al. Hypercoagulability inhibits monocyte transendothelial migration through protease-activated receptor-1-, phospholipase-Cbeta-, phosphoinositide 3-kinase-, and nitric oxide-dependent signaling in monocytes and promotes plaque stability. Circulation 2009; 120 (09) 774-784
    CrossrefPubMedGoogle Scholar
  • 47 Borissoff JI, Spronk HM, ten Cate H. The hemostatic system as a modulator of atherosclerosis. N Engl J Med 2011; 364 (18) 1746-1760
    CrossrefPubMedGoogle Scholar
  • 48 Camerer E, Barker A, Duong DN. , et al. Local protease signaling contributes to neural tube closure in the mouse embryo. Dev Cell 2010; 18 (01) 25-38
    CrossrefPubMedGoogle Scholar
  • 49 Jones SM, Mann A, Conrad K. , et al. PAR2 (protease-activated receptor 2) deficiency attenuates atherosclerosis in mice. Arterioscler Thromb Vasc Biol 2018; 38 (06) 1271-1282
    CrossrefPubMedGoogle Scholar
  • 50 Hara T, Phuong PT, Fukuda D. , et al. Protease-activated receptor-2 plays a critical role in vascular inflammation and atherosclerosis in apolipoprotein E-deficient mice. Circulation 2018; 138 (16) 1706-1719
    CrossrefPubMedGoogle Scholar
  • 51 Zuo P, Zhou Q, Zuo Z, Wang X, Chen L, Ma G. Effects of the factor Xa inhibitor, fondaparinux, on the stability of atherosclerotic lesions in apolipoprotein E-deficient mice. Circ J 2015; 79 (11) 2499-2508
    CrossrefPubMedGoogle Scholar
  • 52 Hara T, Fukuda D, Tanaka K. , et al. Rivaroxaban, a novel oral anticoagulant, attenuates atherosclerotic plaque progression and destabilization in ApoE-deficient mice. Atherosclerosis 2015; 242 (02) 639-646
    CrossrefPubMedGoogle Scholar
  • 53 Maas C, Renné T. Regulatory mechanisms of the plasma contact system. Thromb Res 2012; 129 (Suppl. 02) S73-S76
    CrossrefPubMedGoogle Scholar
  • 54 Renné T, Pozgajová M, Grüner S. , et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med 2005; 202 (02) 271-281
    CrossrefPubMedGoogle Scholar
  • 55 Evangelho JS, Casali KR, Campos C, De Angelis K, Veiga AB, Rigatto K. Hypercholesterolemia magnitude increases sympathetic modulation and coagulation in LDLr knockout mice. Auton Neurosci 2011; 159 (1–2): 98-103
    CrossrefPubMedGoogle Scholar
  • 56 Borissoff JI, Heeneman S, Kilinç E. , et al. Early atherosclerosis exhibits an enhanced procoagulant state. Circulation 2010; 122 (08) 821-830
    CrossrefPubMedGoogle Scholar
  • 57 Vorlova S, Koch M, Manthey HD. , et al. Coagulation factor XII induces pro-inflammatory cytokine responses in macrophages and promotes atherosclerosis in mice. Thromb Haemost 2017; 117 (01) 176-187
    Article in Thieme ConnectPubMedGoogle Scholar
  • 58 Rana R, Huang T, Koukos G. , et al. Noncanonical matrix metalloprotease 1-protease-activated receptor 1 signaling drives progression of atherosclerosis. Arterioscler Thromb Vasc Biol 2018; 38 (06) 1368-1380
    CrossrefPubMedGoogle Scholar
  • 59 Reidy K, Kang HM, Hostetter T, Susztak K. Molecular mechanisms of diabetic kidney disease. J Clin Invest 2014; 124 (06) 2333-2340
    CrossrefPubMedGoogle Scholar
  • 60 Sommeijer DW, Florquin S, Hoedemaker I, Timmerman JJ, Reitsma PH, Ten Cate H. Renal tissue factor expression is increased in streptozotocin-induced diabetic mice. Nephron Exp Nephrol 2005; 101 (03) e86-e94
    CrossrefPubMedGoogle Scholar
  • 61 Sumi A, Yamanaka-Hanada N, Bai F, Makino T, Mizukami H, Ono T. Roles of coagulation pathway and factor Xa in the progression of diabetic nephropathy in db/db mice. Biol Pharm Bull 2011; 34 (06) 824-830
    CrossrefPubMedGoogle Scholar
  • 62 Isermann B, Vinnikov IA, Madhusudhan T. , et al. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat Med 2007; 13 (11) 1349-1358
    CrossrefPubMedGoogle Scholar
  • 63 Mormile A, Veglio M, Gruden G. , et al. Physiological inhibitors of blood coagulation and prothrombin fragment F 1 + 2 in type 2 diabetic patients with normoalbuminuria and incipient nephropathy. Acta Diabetol 1996; 33 (03) 241-245
    CrossrefPubMedGoogle Scholar
  • 64 Matsumoto K, Yano Y, Gabazza EC. , et al. Inverse correlation between activated protein C generation and carotid atherosclerosis in Type 2 diabetic patients. Diabet Med 2007; 24 (12) 1322-1328
    CrossrefPubMedGoogle Scholar
  • 65 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 (03) 337-346
    CrossrefPubMedGoogle Scholar
  • 66 Madhusudhan T, Wang H, Straub BK. , et al. Cytoprotective signaling by activated protein C requires protease-activated receptor-3 in podocytes. Blood 2012; 119 (03) 874-883
    CrossrefPubMedGoogle Scholar
  • 67 Madhusudhan T, Wang H, Ghosh S. , et al. Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function. Blood 2017; 130 (12) 1445-1455
    CrossrefPubMedGoogle Scholar
  • 68 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 U S A 2013; 110 (02) 648-653
    CrossrefPubMedGoogle Scholar
  • 69 Madhusudhan T, Wang H, Dong W. , et al. Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy. Nat Commun 2015; 6: 6496
    CrossrefPubMedGoogle Scholar
  • 70 Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 2002; 296 (5574): 1880-1882
    CrossrefPubMedGoogle Scholar
  • 71 Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood 2007; 109 (08) 3161-3172
    CrossrefPubMedGoogle Scholar
  • 72 Rezaie AR. The occupancy of endothelial protein C receptor by its ligand modulates the par-1 dependent signaling specificity of coagulation proteases. IUBMB Life 2011; 63 (06) 390-396
    CrossrefPubMedGoogle Scholar
  • 73 Mosnier LO, Sinha RK, Burnier L, Bouwens EA, Griffin JH. Biased agonism of protease-activated receptor 1 by activated protein C caused by noncanonical cleavage at Arg46. Blood 2012; 120 (26) 5237-5246
    CrossrefPubMedGoogle Scholar
  • 74 Wang H, Madhusudhan T, He T. , et al. Low but sustained coagulation activation ameliorates glucose-induced podocyte apoptosis: protective effect of factor V Leiden in diabetic nephropathy. Blood 2011; 117 (19) 5231-5242
    CrossrefPubMedGoogle Scholar
  • 75 Sharma R, Waller AP, Agrawal S. , et al. Thrombin-induced podocyte injury is protease-activated receptor dependent. J Am Soc Nephrol 2017; 28 (09) 2618-2630
    CrossrefPubMedGoogle Scholar
  • 76 Oe Y, Hayashi S, Fushima T. , et al. Coagulation factor Xa and protease-activated receptor 2 as novel therapeutic targets for diabetic nephropathy. Arterioscler Thromb Vasc Biol 2016; 36 (08) 1525-1533
    CrossrefPubMedGoogle Scholar
  • 77 Kumar Vr S, Darisipudi MN, Steiger S. , et al. Cathepsin S cleavage of protease-activated receptor-2 on endothelial cells promotes microvascular diabetes complications. J Am Soc Nephrol 2016; 27 (06) 1635-1649
    CrossrefPubMedGoogle Scholar
  • 78 Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest 2017; 127 (01) 1-4
    CrossrefPubMedGoogle Scholar
  • 79 Larsen CM, Faulenbach M, Vaag A. , et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 2007; 356 (15) 1517-1526
    CrossrefPubMedGoogle Scholar
  • 80 Masters SL, Dunne A, Subramanian SL. , et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat Immunol 2010; 11 (10) 897-904
    CrossrefPubMedGoogle Scholar
  • 81 Eguchi K, Nagai R. Islet inflammation in type 2 diabetes and physiology. J Clin Invest 2017; 127 (01) 14-23
    CrossrefPubMedGoogle Scholar
  • 82 Rothmeier AS, Marchese P, Petrich BG. , et al. Caspase-1-mediated pathway promotes generation of thromboinflammatory microparticles. J Clin Invest 2015; 125 (04) 1471-1484
    CrossrefPubMedGoogle Scholar
  • 83 Furlan-Freguia C, Marchese P, Gruber A, Ruggeri ZM, Ruf W. P2 × 7 receptor signaling contributes to tissue factor-dependent thrombosis in mice. J Clin Invest 2011; 121 (07) 2932-2944
    CrossrefPubMedGoogle Scholar
  • 84 Johansson H, Lukinius A, Moberg L. , et al. Tissue factor produced by the endocrine cells of the islets of Langerhans is associated with a negative outcome of clinical islet transplantation. Diabetes 2005; 54 (06) 1755-1762
    CrossrefPubMedGoogle Scholar
  • 85 Jayashree B, Bibin YS, Prabhu D. , et al. Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes. Mol Cell Biochem 2014; 388 (1–2): 203-210
    CrossrefPubMedGoogle Scholar
  • 86 Thaiss CA, Levy M, Grosheva I. , et al. Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection. Science 2018; 359 (6382): 1376-1383
    CrossrefPubMedGoogle Scholar
  • 87 Reinhardt C, Bergentall M, Greiner TU. , et al. Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling. Nature 2012; 483 (7391): 627-631
    PubMedGoogle Scholar
  • 88 Vergnolle N. Protease inhibition as new therapeutic strategy for GI diseases. Gut 2016; 65 (07) 1215-1224
    CrossrefPubMedGoogle Scholar
  • 89 Ghorpade DS, Ozcan L, Zheng Z. , et al. Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance. Nature 2018; 555 (7698): 673-677
    PubMedGoogle Scholar
  • 90 Cheng RKY, Fiez-Vandal C, Schlenker O. , et al. Structural insight into allosteric modulation of protease-activated receptor 2. Nature 2017; 545 (7652): 112-115
    CrossrefPubMedGoogle Scholar
  • 91 Zhang C, Srinivasan Y, Arlow DH. , et al. High-resolution crystal structure of human protease-activated receptor 1. Nature 2012; 492 (7429): 387-392
    CrossrefPubMedGoogle Scholar
  • 92 Gurbel PA, Bliden KP, Turner SE. , et al. Cell-penetrating pepducin therapy targeting PAR1 in subjects with coronary artery disease. Arterioscler Thromb Vasc Biol 2016; 36 (01) 189-197
    CrossrefPubMedGoogle Scholar
  • 93 Zhang P, Leger AJ, Baleja JD. , et al. Allosteric activation of a G protein-coupled receptor with cell-penetrating receptor mimetics. J Biol Chem 2015; 290 (25) 15785-15798
    CrossrefPubMedGoogle Scholar
  • 94 Zhang P, Gruber A, Kasuda S. , et al. Suppression of arterial thrombosis without affecting hemostatic parameters with a cell-penetrating PAR1 pepducin. Circulation 2012; 126 (01) 83-91
    CrossrefPubMedGoogle Scholar
  • 95 Lim J, Iyer A, Liu L. , et al. Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism. FASEB J 2013; 27 (12) 4757-4767
    CrossrefPubMedGoogle Scholar