Subscribe to RSS
DOI: 10.1160/TH14-10-0899
Proteolytically active ADAM10 and ADAM17 carried on membrane microvesicles in human abdominal aortic aneurysms
Publication History
Received:
31 October 2014
Accepted after major revision:
01 July 2015
Publication Date:
30 November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201506/lookinside/thumbnails/10-1160-th14-10-0899-1.jpg)
Summary
The intraluminal thrombus (ILT) of human abdominal aortic aneurysm (AAA) has been suggested to damage the underlying aortic wall, but previous work found scant activity of soluble proteases in the abluminal layer of the ILT, adjacent to the aneurysm. We hypothesised that transmembrane proteases carried by membrane microvesicles (MV) from dying cells remain active in the abluminal ILT. ILTs and AAA segments collected from 21 patients during surgical repair were assayed for two major transmembrane proteases, ADAM10 (a disintegrin and metalloprotease-10) and ADAM17. We also exposed cultured cells to tobacco smoke and assessed ADAM10 and ADAM17 expression and release on MVs. Immunohistochemistry showed abundant ADAM10 and ADAM17 protein in the ILT and underlying aneurysmal aorta. Domain-specific antibodies indicated both transmembrane and shed ADAM17. Importantly, ADAM10 and ADAM 17 in the abluminal ILT were enzymatically active. Electron microscopy of abluminal ILT and aortic wall showed MVs with ADAM10 and ADAM17. By flow cytometry, ADAM-positive microvesicles from abluminal ILT carried the neutrophil marker CD66, but not the platelet marker CD61. Cultured HL60 neutrophils exposed to tobacco smoke extract showed increased ADAM10 and ADAM17 content, cleavage of these molecules into active forms, and release of MVs carrying mature ADAM10 and detectable ADAM17. In conclusion, our results implicate persistent, enzymatically active ADAMs on MVs in the abluminal ILT, adjacent to the aneurysmal wall. The production of ADAM10- and ADAM17-positive MVs from smoke-exposed neutrophils provides a novel molecular mechanism for the vastly accelerated risk of AAA in smokers.
Portions of this work were presented at the Arteriosclerosis, Thrombosis and Vascular Biology 2012 Scientific Sessions, 19 Apr 2012 (ref. 25), and in a doctoral thesis defense February 2013 (ref. 26).
Keywords
Abdominal aortic aneurysm - ADAM10 - ADAM17 - intraluminal thrombus - A disintegrin and matrix metalloproteinase - membrane-bound protease - microparticles - microvesicles* Co-senior authors.
-
References
- 1 Landenhed M, Engstrom G, Gottsater A. et al. Risk profiles for aortic dissection and ruptured or surgically treated aneurysms: a prospective cohort study. J Am Heart Assoc 2015; 04: e001513.
- 2 Brady AR, Thompson SG, Fowkes FG. et al. Participants UKSAT. Abdominal aortic aneurysm expansion: risk factors and time intervals for surveillance. Circulation 2004; 110: 16-21.
- 3 Rizas KD, Ippagunta N, Tilson 3rd. MD. Immune cells and molecular mediators in the pathogenesis of the abdominal aortic aneurysm. Cardiol Rev 2009; 17: 201-210.
- 4 Hans SS, Jareunpoon O, Balasubramaniam M. et al. Size and location of thrombus in intact and ruptured abdominal aortic aneurysms. J Vasc Surg 2005; 41: 584-588.
- 5 Kazi M, Zhu C, Roy J. et al. Difference in matrix-degrading protease expression and activity between thrombus-free and thrombus-covered wall of abdominal aortic aneurysm. Arterioscl Thromb Vasc Biol 2005; 25: 1341-1346.
- 6 Touat Z, Ollivier V, Dai J. et al. Renewal of mural thrombus releases plasma markers and is involved in aortic abdominal aneurysm evolution. Am J Pathol 2006; 168: 1022-1030.
- 7 Houard X, Touat Z, Ollivier V. et al. Mediators of neutrophil recruitment in human abdominal aortic aneurysms. Cardiovasc Res 2009; 82: 532-541.
- 8 Michel JB, Martin-Ventura JL, Egido J. et al. Novel aspects of the pathogenesis of aneurysms of the abdominal aorta in humans. Cardiovasc Res 2011; 90: 18-27.
- 9 Liu J, Sukhova GK, Yang JT. et al. Cathepsin L expression and regulation in human abdominal aortic aneurysm, atherosclerosis, and vascular cells. Atherosclerosis 2006; 184: 302-311.
- 10 Annabi B, Shedid D, Ghosn P. et al. Differential regulation of matrix metalloproteinase activities in abdominal aortic aneurysms. J Vasc Surg 2002; 35: 539-546.
- 11 Folkesson M, Silveira A, Eriksson P. et al. Protease activity in the multi-layered intra-luminal thrombus of abdominal aortic aneurysms. Atherosclerosis 2011; 218: 294-299.
- 12 Parkin E, Harris B. A disintegrin and metalloproteinase (ADAM)-mediated ectodomain shedding of ADAM10. J Neurochem 2009; 108: 1464-1479.
- 13 Giesen PL, Rauch U, Bohrmann B. et al. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci USA 1999; 96: 2311-2315.
- 14 Liu ML, Williams KJ. Microvesicles: potential markers and mediators of endothelial dysfunction. Curr Opin Endocrinol Diabetes Obes 2012; 19: 121-127.
- 15 Millichip MI, Dallas DJ, Wu E. et al. The metallo-disintegrin ADAM10 (MADM) from bovine kidney has type IV collagenase activity in vitro. Biochem Biophys Res Commun 1998; 245: 594-598.
- 16 Edwards DR, Handsley MM, Pennington CJ. The ADAM metalloproteinases. Mol Aspects Med 2008; 29: 258-289.
- 17 Kyriakis JM, Banerjee P, Nikolakaki E. et al. The stress-activated protein kinase subfamily of c-Jun kinases. Nature 1994; 369: 156-160.
- 18 Yoshimura K, Aoki H, Ikeda Y. et al. Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase. Nat Med 2005; 11: 1330-1338.
- 19 Satoh H, Nakamura M, Satoh M. et al. Expression and localization of tumour necrosis factor-alpha and its converting enzyme in human abdominal aortic aneurysm. Clin Sci 2004; 106: 301-306.
- 20 Lindholt JS, Shi GP. Chronic inflammation, immune response, and infection in abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 2006; 31: 453-463.
- 21 Xiong W, MacTaggart J, Knispel R. et al. Blocking TNF-alpha attenuates aneurysm formation in a murine model. J Immunol 2009; 183: 2741-2746.
- 22 Lipp C, Lohoefer F, Reeps C. et al. Expression of a disintegrin and metallopro-tease in human abdominal aortic aneurysms. J Vasc Res 2012; 49: 198-206.
- 23 Scheller J, Chalaris A, Garbers C. et al. ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends Immunol 2011; 32: 380-387.
- 24 Zheng YH, Tian C, Meng Y. et al. Osteopontin stimulates autophagy via integrin/CD44 and p38 MAPK signaling pathways in vascular smooth muscle cells. J Cell Physiol 2012; 227: 127-135.
- 25 Folkesson M, Li C, Swedenborg J, Roy J. et al. Potently proteolytic microvesicles derived from neutrophils are present within the intraluminal thrombus of human abdominal aortic aneurysms. Arterioscl Thromb Vasc Biol 2012; 32 (05) A252.
- 26 Folkesson M. Significance of Intraluminal Thrombus in Abdominal Aortic Aneurysm. PhD thesis. Inst för molekylär medicin och kirurgi / Dept of Molecular Medicine and Surgery, Karolinska Instituet; Stockholm, Sweden: 2013. ISBN:978–91–7457–945–1.
- 27 Qinyang W, Hultenby K, Adlan E. et al. Galanin in adjuvant arthritis in the rat. J Rheumatol 2004; 31: 302-307.
- 28 Boulanger CM, Amabile N, Guerin AP. et al. In vivo shear stress determines circulating levels of endothelial microparticles in end-stage renal disease. Hypertension 2007; 49: 902-908.
- 29 Liu ML, Reilly MP, Casasanto P. et al. Cholesterol enrichment of human monocyte/macrophages induces surface exposure of phosphatidylserine and the release of biologically-active tissue factor-positive microvesicles. Arterioscl Thromb Vasc Biol 2007; 27: 430-435.
- 30 Li M, Yu D, Williams KJ. et al. Tobacco smoke induces the generation of procoagulant microvesicles from human monocytes/macrophages. Arterioscl Thromb Vasc Biol 2010; 30: 1818-1824.
- 31 Li CJ, Liu Y, Chen Y. et al. Novel proteolytic microvesicles released from human macrophages after exposure to tobacco smoke. The Am J Pathol 2013; 182: 1552-1562.
- 32 Anderson R, Stankova L, Bigley RH. et al. Dehydroascorbate uptake as an in vitro biochemical marker of granulocyte differentiation. Cancer Res 1983; 43: 4696-4698.
- 33 Leroyer AS, Isobe H, Leseche G. et al. Cellular origins and thrombogenic activity of microparticles isolated from human atherosclerotic plaques. J Am Coll Cardiol 2007; 49: 772-777.
- 34 Pillay J, den Braber I, Vrisekoop N. et al. In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days. Blood 2010; 116: 625-627.
- 35 Gutwein P, Stoeck A, Riedle S. et al. Cleavage of L1 in exosomes and apoptotic membrane vesicles released from ovarian carcinoma cells. Clin Cancer Res 2005; 11: 2492-2501.
- 36 Effenberger T, von der Heyde J, Bartsch K. et al. Senescence-associated release of transmembrane proteins involves proteolytic processing by ADAM17 and microvesicle shedding. FASEB J 2014; 28: 4847-4856.
- 37 Canault M, Leroyer AS, Peiretti F. et al. Microparticles of human atherosclerotic plaques enhance the shedding of the tumor necrosis factor-alpha converting enzyme/ADAM17 substrates, tumor necrosis factor and tumor necrosis factor receptor-1. Am J Pathol 2007; 171: 1713-1723.
- 38 Martinez-Pinna R, Madrigal-Matute J, Tarin C. et al. Proteomic analysis of intraluminal thrombus highlights complement activation in human abdominal aortic aneurysms. Arterioscl Thromb Vasc Biol 2013; 33: 2013-2020.