Proprotein convertase furin is a driver and potential therapeutic target in proliferative diabetic retinopathy.
Animals
Diabetes Mellitus, Experimental
/ metabolism
Diabetic Retinopathy
/ metabolism
Endothelial Cells
/ metabolism
Epiretinal Membrane
Furin
/ metabolism
Humans
Intercellular Adhesion Molecule-1
/ metabolism
NF-kappa B
/ metabolism
Neovascularization, Pathologic
/ metabolism
Proprotein Convertases
/ metabolism
Rats
Tumor Necrosis Factor-alpha
/ metabolism
Vitreous Body
/ metabolism
angiogenesis
furin
inflammation
proliferative diabetic retinopathy
proprotein convertase
Journal
Clinical & experimental ophthalmology
ISSN: 1442-9071
Titre abrégé: Clin Exp Ophthalmol
Pays: Australia
ID NLM: 100896531
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
revised:
01
03
2022
received:
11
11
2021
accepted:
03
03
2022
pubmed:
25
3
2022
medline:
10
8
2022
entrez:
24
3
2022
Statut:
ppublish
Résumé
Furin converts inactive proproteins into bioactive forms. By activating proinflammatory and proangiogenic factors, furin might play a role in pathophysiology of proliferative diabetic retinopathy (PDR). We studied vitreous samples from PDR and nondiabetic patients, epiretinal membranes from PDR patients, retinal microvascular endothelial cells (HRMECs), retinal Müller cells and rat retinas by ELISA, Western blot analysis, immunohistochemistry and immunofluorescence microscopy. We performed in vitro angiogenesis assays and assessed adherence of monocytes to HRMECs. Furin levels were significantly increased in PDR vitreous samples. In epiretinal membranes, immunohistochemistry analysis revealed furin expression in monocytes/macrophages, vascular endothelial cells and myofibroblasts. Furin was significantly upregulated in diabetic rat retinas. Hypoxia and TNF-α induced significant upregulation of furin in Müller cells and HRMECs. Furin induced upregulation of phospho-ERK1/2, p65 subunit of NF-κB, ADAM17 and MCP-1 in cultured Müller cells and phospho-ERK1/2 in cultured HRMECs and induced HRMECs migration. Treatment of monocytes with furin significantly increased their adhesion to HRMECs. Intravitreal administration of furin in normal rats induced significant upregulation of p65 subunit of NF-κB, phospho-ERK1/2 and ICAM-1 in the retina. Inhibition of furin with dec-CMK significantly decreased levels of MCP-1 in culture medium of Müller cells and HRMECs and significantly attenuated TNF-α-induced upregulation of p65 subunit of NF-κB, ICAM-1 and VCAM-1 in HRMECs. Dec-CMK significantly decreased adherence of monocytes to HRMECs and TNF-α-induced upregulation of adherence of monocytes to HRMECs. Treatment of HRMECs with dec-CMK significantly attenuated migration of HRMECs. Furin is a potential driver molecule of PDR-associated inflammation and angiogenesis.
Sections du résumé
BACKGROUND
Furin converts inactive proproteins into bioactive forms. By activating proinflammatory and proangiogenic factors, furin might play a role in pathophysiology of proliferative diabetic retinopathy (PDR).
METHODS
We studied vitreous samples from PDR and nondiabetic patients, epiretinal membranes from PDR patients, retinal microvascular endothelial cells (HRMECs), retinal Müller cells and rat retinas by ELISA, Western blot analysis, immunohistochemistry and immunofluorescence microscopy. We performed in vitro angiogenesis assays and assessed adherence of monocytes to HRMECs.
RESULTS
Furin levels were significantly increased in PDR vitreous samples. In epiretinal membranes, immunohistochemistry analysis revealed furin expression in monocytes/macrophages, vascular endothelial cells and myofibroblasts. Furin was significantly upregulated in diabetic rat retinas. Hypoxia and TNF-α induced significant upregulation of furin in Müller cells and HRMECs. Furin induced upregulation of phospho-ERK1/2, p65 subunit of NF-κB, ADAM17 and MCP-1 in cultured Müller cells and phospho-ERK1/2 in cultured HRMECs and induced HRMECs migration. Treatment of monocytes with furin significantly increased their adhesion to HRMECs. Intravitreal administration of furin in normal rats induced significant upregulation of p65 subunit of NF-κB, phospho-ERK1/2 and ICAM-1 in the retina. Inhibition of furin with dec-CMK significantly decreased levels of MCP-1 in culture medium of Müller cells and HRMECs and significantly attenuated TNF-α-induced upregulation of p65 subunit of NF-κB, ICAM-1 and VCAM-1 in HRMECs. Dec-CMK significantly decreased adherence of monocytes to HRMECs and TNF-α-induced upregulation of adherence of monocytes to HRMECs. Treatment of HRMECs with dec-CMK significantly attenuated migration of HRMECs.
CONCLUSIONS
Furin is a potential driver molecule of PDR-associated inflammation and angiogenesis.
Substances chimiques
NF-kappa B
0
Tumor Necrosis Factor-alpha
0
Intercellular Adhesion Molecule-1
126547-89-5
Proprotein Convertases
EC 3.4.21.-
FURIN protein, human
EC 3.4.21.75
Furin
EC 3.4.21.75
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
632-652Informations de copyright
© 2022 Royal Australian and New Zealand College of Ophthalmologists.
Références
Abu El-Asrar AM, Mohammad G, Nawaz MI, et al. Relationship between vitreous levels of matrix metalloproteinases and vascular endothelial growth factor in proliferative diabetic retinopathy. PLoS One. 2013;8(12):e85857.
Abu El-Asrar AM, Ahmad A, Siddiquei MM, et al. The proinflammatory and proangiogenic macrophage migration inhibitory factor is a potential regulator in proliferative diabetic retinopathy. Front Immunol. 2019;10:2752. doi:10.3389/fimmu.2019.02752
Abu El-Asrar AM, Alam K, Garcia-Ramirez M, et al. Association of HMGB1 with oxidative stress markers and regulators in PDR. Mol Vis. 2017;23:853-871.
Abu El-Asrar AM, Nawaz MI, Ahmad A, et al. CD146/soluble CD146 pathway is a novel biomarker of angiogenesis and inflammation in proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci. 2021;62:32.
Abu El-Asrar AM, Nawaz MI, Ahmad A, et al. Evaluation of proteoforms of the transmembrane chemokines CXCL16 and CX3CL1, their receptors, and their processing metalloproteinases ADAM10 and ADAM17 in proliferative diabetic retinopathy. Front Immunol. 2021;11:601639.
Rezzola S, Loda A, Corsini M, et al. Angiogenesis-inflammation cross talk in diabetic retinopathy: novel insights from the chick embryo chorioallantoic membrane/human vitreous platform. Front Immunol. 2020;11:581288.
Abu El-Asrar AM, Mohammad G, Allegaert E, et al. Matrix metalloproteinase-14 is a biomarker of angiogenic activity in proliferative diabetic retinopathy. Mol Vis. 2018;24:394-406
Forrester JV, Kuffova L, Delibegovic M. The role of inflammation in diabetic retinopathy. Front Immunol. 2020;11:583687.
Jaaks P, Bernasconi M. The proprotein convertase furin in tumour progression. Int J Cancer. 2017;141:654-663.
Bassi DE, Fu J, Lopez de Cicco R, Klein-Szanto AJ. Proprotein convertases: "master switches" in the regulation of tumor growth and progression. Mol Carcinog. 2005;44:151-161.
Khatib AM, Siegfried G, Chrétien M, Metrakos P, Seidah NG. Proprotein convertases in tumor progression and malignancy: novel targets in cancer therapy. Am J Pathol. 2002;160:1921-1935.
Jaaks P, D'Alessandro V, Grob N, et al. The proprotein convertase furin contributes to rhabdomyosarcoma malignancy by promoting vascularization, migration and invasion. PLoS One. 2016;11(8):e0161396.
Chen C, Gupta P, Parashar D, et al. ERBB3-induced furin promotes the progression and metastasis of ovarian cancer via the IGF1R/STAT3 signaling axis. Oncogene. 2020;39:2921-2933.
Garten W, Hallenberger S, Ortmann D, et al. Processing of viral glycoproteins by the subtilisin-like endoprotease furin and its inhibition by specific peptidylchloroalkylketones. Biochimie. 1994;76:217-225.
Maquoi E, Noël A, Frankenne F, Angliker H, Murphy G, Foidart JM. Inhibition of matrix metalloproteinase 2 maturation and HT1080 invasiveness by a synthetic furin inhibitor. FEBS Lett. 1998;424:262-266.
Coppola JM, Bhojani MS, Ross BD, Rehemtulla A. A small-molecule furin inhibitor inhibits cancer cell motility and invasiveness. Neoplasia. 2008;10:363-370.
Bassi DE, Zhang J, Cenna J, Litwin S, Cukierman E, Klein-Szanto AJ. Proprotein convertase inhibition results in decreased skin cell proliferation, tumorigenesis, and metastasis. Neoplasia. 2010;12:516-526.
Couture F, Kwiatkowska A, Dory YL, Day R. Therapeutic uses of furin and its inhibitors: a patent review. Expert Opin Ther Pat. 2015;25:379-396.
Vidricaire G, Denault JB, Leduc R. Characterization of a secreted form of human furin endoprotease. Biochem Biophys Res Commun. 1993;195:1011-1018.
Plaimauer B, Mohr G, Wernhart W, Himmelspach M, Dorner F, Schlokat U. 'Shed' furin: mapping of the cleavage determinants and identification of its C-terminus. Biochem J. 2001;354(Pt 3):689-695.
Fernandez C, Rysä J, Almgren P, et al. Plasma levels of the proprotein convertase furin and incidence of diabetes and mortality. J Intern Med. 2018;284:377-387.
Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480-1487.
Shapiro J, Sciaky N, Lee J, Bosshart H, Angeletti RH, Bonifacino JS. Localization of endogenous furin in cultured cell lines. J Histochem Cytochem. 1997;45:3-12.
Pateras IS, Cooks T. Determination of polarization of resident macrophages and their effect on the tumor microenvironment. Methods Mol Biol. 2019;1928:101-112.
Umansky V, Adema GJ, Baran J, et al. Interactions among myeloid regulatory cells in cancer. Cancer Immunol Immunother. 2019;68:645-660.
Zhao G, Yang W, Wu J, et al. Influence of a coronary artery disease-associated genetic variant on furin expression and effect of furin on macrophage behavior. Arterioscler Thromb Vasc Biol. 2018;38:1837-1844.
Turpeinen H, Raitoharju E, Oksanen A, et al. Proprotein convertases in human atherosclerotic plaques: the overexpression of FURIN and its substrate cytokines BAFF and APRIL. Atherosclerosis. 2011;219:799-806.
Stawowy P, Kallisch H, Borges Pereira Stawowy N, et al. Immunohistochemical localization of subtilisin/kexin-like proprotein convertases in human atherosclerosis. Virchows Arch. 2005;446:351-359.
Stawowy P, Meyborg H, Stibenz D, et al. Furin-like proprotein convertases are central regulators of the membrane type matrix metalloproteinase-pro-matrix metalloproteinase-2 proteolytic cascade in atherosclerosis. Circulation. 2005;111:2820-2827.
Yakala GK, Cabrera-Fuentes HA, Crespo-Avilan GE, et al. Furin inhibition reduces vascular remodeling and atherosclerotic lesion progression in mice. Arterioscler Thromb Vasc Biol. 2019;39:387-401.
Vähätupa M, Cordova ZM, Barker H, et al. Furin deficiency in myeloid cells leads to attenuated revascularization in a mouse-model of oxygen-induced retinopathy. Exp Eye Res. 2018;166:160-167.
Yang X, Yang W, McVey DG, et al. Furin expression in vascular endothelial cells is modulated by a coronary artery disease-associated genetic variant and influences monocyte transendothelial migration. J Am Heart Assoc. 2020;9(4):e014333. doi:10.1161/JAHA.119.014333
Miyamoto K, Khosrof S, Bursell SE, et al. Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc Natl Acad Sci U S A. 1999;96:10836-10841.
Baumann J, Huang SF, Gassmann M, Tsao CC, Ogunshola OO. Furin inhibition prevents hypoxic and TGFβ-mediated blood-brain barrier disruption. Exp Cell Res. 2019;383(2):111503. doi:10.1016/j.yexcr.2019.111503
Siegfried G, Basak A, Cromlish JA, et al. The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis. J Clin Invest. 2003;111:1723-1732.
McColl BK, Paavonen K, Karnezis T, et al. Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2. FASEB J. 2007;21:1088-1098.
Bringmann A, Pannicke T, Grosche J, et al. Müller cells in the healthy and diseased retina. Prog Retin Eye Res. 2006;25:397-424.
McMahon S, Grondin F, McDonald PP, Richard DE, Dubois CM. Hypoxia-enhanced expression of the proprotein convertase furin is mediated by hypoxia-inducible factor-1: impact on the bioactivation of proproteins. J Biol Chem. 2005;280:6561-6569.
Rana AK, Li Y, Dang Q, Yang F. Monocytes in rheumatoid arthritis: circulating precursors of macrophages and osteoclasts and, their heterogeneity and plasticity role in RA pathogenesis. Int Immunopharmacol. 2018;65:348-359.
He Z, Thorrez L, Siegfried G, et al. The proprotein convertase furin is a pro-oncogenic driver in KRAS and BRAF driven colorectal cancer. Oncogene. 2020;39:3571-3587.