Profiling of atherosclerotic lesions by gene and tissue microarrays reveals pcsk6 as a novel protease in unstable carotid atherosclerosis

Arteriosclerosis, Thrombosis, and Vascular Biology

Volumn 33, Issue 10, 2013, Pages 2432-2443

  Perisic, Ljubica ^a   Hedin, Erika ^a   Razuvaev, Anton ^a   Lengquist, Mariette ^a   Osterholm, Cecilia ^a   Folkersen, Lasse ^c   Gillgren, Peter ^d   Paulsson Berne, Gabrielle ^b   Ponten, Fredrik ^e   Odeberg, Jacob ^b,f   Hedin, Ulf ^a  

^a KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

^b KAROLINSKA INSTITUTE   (Sweden)

^c NOVO NORDISK A S   (Denmark)

^d STOCKHOLM SÖDER HOSPITAL   (Sweden)

^e UPPSALA UNIVERSITY   (Sweden)

^f ROYAL INSTITUTE OF TECHNOLOGY   (Sweden)

Author keywords

atherosclerosis; carotid stenosis; muscle, smooth; symptomatic carotid stenosis

Indexed keywords

ACYL COENZYME A DESATURASE; ADRENOMEDULLIN; ALPHA SMOOTH MUSCLE ACTIN; CALGRANULIN B; CARBONATE DEHYDRATASE XII; CARBOXYPEPTIDASE; CATHEPSIN B; CATHEPSIN L; CATHEPSIN X; CD137 ANTIGEN; CD36 ANTIGEN; ENDOTHELIN RECEPTOR; ENOLASE; GLUTAMATE AMMONIA LIGASE; GLUTAREDOXIN; HEME OXYGENASE 1; KEXIN; LAMIN B; LEGUMAIN; LYSOSOME ASSOCIATED MEMBRANE PROTEIN 2; MITOGENIC AGENT; OPSIN; PCSK6 PROTEIN; PLEXIN; PROTEIN; SPHINGOMYELIN PHOSPHODIESTERASE; SUBTILISIN; SYNDECAN 2; TENASCIN; UNCLASSIFIED DRUG; VASCULOTROPIN A;

ARTICLE; CAROTID ATHEROSCLEROSIS; CAROTID ENDARTERECTOMY; EXTRACELLULAR MATRIX; HUMAN; HUMAN CELL; IMMUNOHISTOCHEMISTRY; IN VITRO STUDY; MAJOR CLINICAL STUDY; MICROARRAY ANALYSIS; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN EXPRESSION; REAL TIME POLYMERASE CHAIN REACTION; SMOOTH MUSCLE FIBER; STAINING; TISSUE MICROARRAY; UPREGULATION;

ATHEROSCLEROSIS; CAROTID STENOSIS; MUSCLE, SMOOTH; SYMPTOMATIC CAROTID STENOSIS;

ASYMPTOMATIC DISEASES; CAROTID STENOSIS; CELLS, CULTURED; CYTOKINES; EXTRACELLULAR MATRIX; FIBROSIS; GENE EXPRESSION PROFILING; HUMANS; IMMUNOHISTOCHEMISTRY; INFLAMMATION MEDIATORS; MUSCLE, SMOOTH, VASCULAR; MYOCYTES, SMOOTH MUSCLE; OLIGONUCLEOTIDE ARRAY SEQUENCE ANALYSIS; PLAQUE, ATHEROSCLEROTIC; PROPROTEIN CONVERTASES; REAL-TIME POLYMERASE CHAIN REACTION; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; RNA, MESSENGER; RUPTURE, SPONTANEOUS; SERINE ENDOPEPTIDASES; TISSUE ARRAY ANALYSIS; UP-REGULATION;

EID: 84885068480     PISSN: 10795642     EISSN: 15244636     Source Type: Journal    
DOI: 10.1161/ATVBAHA.113.301743     Document Type: Article

References (51)

1. Naylor AR. Time is brain! Surgeon. 2007;5:23-30
2. Koenig W, Khuseyinova N. Biomarkers of atherosclerotic plaque instability and rupture. Arterioscler Thromb Vasc Biol. 2007;27:15-26
3. Libby P. Multiple mechanisms of thrombosis complicating atherosclerotic plaques. Clin Cardiol. 2000;23 (suppl 6):VI-3-VI-7
4. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol. 2006;47(8 suppl):C13-C18
5. Davies MJ, Richardson PD, Woolf N, Katz DR, Mann J. Risk of thrombosis in human atherosclerotic plaques: Role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J. 1993;69:377-381
6. Rothwell PM. Medical and surgical management of symptomatic carotid stenosis. Int J Stroke. 2006;1:140-149
7. Virmani R, Finn AV, Kolodgie FD. Carotid plaque stabilization and progression after stroke or TIA. Arterioscler Thromb Vasc Biol. 2009;29:3-6
8. Peeters W, Hellings WE, De Kleijn DP, De Vries JP, Moll FL, Vink A, Pasterkamp G. Carotid atherosclerotic plaques stabilize after stroke: Insights into the natural process of atherosclerotic plaque stabilization. Arterioscler Thromb Vasc Biol. 2009;29:128-133
9. Verhoeven BA, Velema E, Schoneveld AH, De Vries JP, De Bruin P, Seldenrijk CA, De Kleijn DP, Busser E, Van Der Graaf Y, Moll F, Pasterkamp G. Athero-express: Differential atherosclerotic plaque expression of mRNA and protein in relation to cardiovascular events and patient characteristics. Rationale and design. Eur J Epidemiol. 2004;19:1127-1133
10. Razuvaev A, Ekstrand J, Folkersen L, Agardh H, Markus D, Swedenborg J, Hansson GK, Gabrielsen A, Paulsson-Berne G, Roy J, Hedin U. Correlations between clinical variables and gene-expression profiles in carotid plaque instability. Eur J Vasc Endovasc Surg. 2011;42:722-730
11. Hurks R, Peeters W, Derksen WJ, Hellings WE, Hoefer IE, Moll FL, De Kleijn DP, Pasterkamp G. Biobanks and the search for predictive biomarkers of local and systemic outcome in atherosclerotic disease. Thromb Haemost. 2009;101:48-54
12. Folkersen L, Persson J, Ekstrand J, Agardh HE, Hansson GK, Gabrielsen A, Hedin U, Paulsson-Berne G. Prediction of ischemic events on the basis of transcriptomic and genomic profiling in patients undergoing carotid endarterectomy. Mol Med. 2012;18:669-675
13. Kim SH, Kim DM, Shim H, Choi J, Park SH, Song SM, Shin YH, Choi D. Application of tissue microarray for atherectomized tissues from peripheral arterial disease. Pathol Res Pract. 2011;207:568-572
14. Halushka MK, Cornish TC, Lu J, Selvin S, Selvin E. Creation, validation, and quantitative analysis of protein expression in vascular tissue microarrays. Cardiovasc Pathol. 2010;19:136-146
15. Halushka MK, Selvin E, Lu J, Macgregor AM, Cornish TC. Use of human vascular tissue microarrays for measurement of advanced glycation endproducts. J Histochem Cytochem. 2009;57:559-566
16. Kononen J, Bubendorf L, Kallioniemi A, Bärlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP. Tissue microarrays for high-Throughput molecular profiling of tumor specimens. Nat Med. 1998;4:844-847
17. Takikita M, Chung JY, Hewitt SM. Tissue microarrays enabling highthroughput molecular pathology. Curr Opin Biotechnol. 2007;18:318-325
18. Osterholm C, Folkersen L, Lengquist M, Pontén F, Renné T, Li J, Hedin U. Increased expression of heparanase in symptomatic carotid atherosclerosis. Atherosclerosis. 2013;226:67-73
19. Turpeinen H, Raitoharju E, Oksanen A, Oksala N, Levula M, Lyytikäinen LP, Järvinen O, Creemers JW, Kähönen M, Laaksonen R, Pelto-Huikko M, Lehtimäki T, Pesu M. Proprotein convertases in human atherosclerotic plaques: The overexpression of FURIN and its substrate cytokines BAFF and APRIL. Atherosclerosis. 2011;219:799-806
20. Hedin U, Bottger BA, Forsberg E, Johansson S, Thyberg J. Diverse effects of fibronectin and laminin on phenotypic properties of cultured arterial smooth muscle cells. J Cell Biol. 1988;107:307-319
21. Hedin U, Roy J, Tran PK. Control of smooth muscle cell proliferation in vascular disease. Curr Opin Lipidol. 2004;15:559-565
22. de Kleijn DP, Moll FL, Hellings WE, et al. Local atherosclerotic plaques are a source of prognostic biomarkers for adverse cardiovascular events. Arterioscler Thromb Vasc Biol. 2010;30:612-619
23. Diez D, Wheelock AM, Goto S, Haeggström JZ, Paulsson-Berne G, Hansson GK, Hedin U, Gabrielsen A, Wheelock CE. The use of network analyses for elucidating mechanisms in cardiovascular disease. Mol Biosyst. 2010;6:289-304
24. Vemuganti R, Dempsey RJ. Carotid atherosclerotic plaques from symptomatic stroke patients share the molecular fingerprints to develop in a neoplastic fashion: A microarray analysis study. Neuroscience. 2005;131:359-374
25. Türeyen K, Vemuganti R, Salamat MS, Dempsey RJ. Increased angiogenesis and angiogenic gene expression in carotid artery plaques from symptomatic stroke patients. Neurosurgery. 2006;58:971-977; discussion 971
26. Ijäs P, Nuotio K, Saksi J, Soinne L, Saimanen E, Karjalainen-Lindsberg ML, Salonen O, Sarna S, Tuimala J, Kovanen PT, Kaste M, Lindsberg PJ. Microarray analysis reveals overexpression of CD163 and HO-1 in symptomatic carotid plaques. Arterioscler Thromb Vasc Biol. 2007;27:154-160
27. King A. Lipids. Antibodies against PCSK9-A new era of therapy. Nat Rev Cardiol. 2013;10:1
28. Maxwell KN, Breslow JL. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci U S A. 2004;101:7100-7105
29. Klee EW, Bondar OP, Goodmanson MK, Dyer RB, Erdogan S, Bergstralh EJ, Bergen HR III, Sebo TJ, Klee GG. Candidate serum biomarkers for prostate adenocarcinoma identified by mRNA differences in prostate tissue and verified with protein measurements in tissue and blood. Clin Chem. 2012;58:599-609
30. Levesque C, Fugère M, Kwiatkowska A, Couture F, Desjardins R, Routhier S, Moussette P, Prahl A, Lammek B, Appel JR, Houghten RA, D'Anjou F, Dory YL, Neugebauer W, Day R. The Multi-Leu peptide inhibitor discriminates between PACE4 and furin and exhibits antiproliferative effects on prostate cancer cells. J Med Chem. 2012;55:10501-10511
31. Stawowy P, Fleck E. Proprotein convertases furin and PC5: Targeting atherosclerosis and restenosis at multiple levels. J Mol Med (Berl). 2005;83:865-875
32. Stawowy P, Meyborg H, Stibenz D, Borges Pereira Stawowy N, Roser M, Thanabalasingam U, Veinot JP, Chrétien M, Seidah NG, Fleck E, Graf K. 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
33. Stawowy P, Marcinkiewicz J, Graf K, Seidah N, Chrétien M, Fleck E, Marcinkiewicz M. Selective expression of the proprotein convertases furin, pc5, and pc7 in proliferating vascular smooth muscle cells of the rat aorta in vitro. J Histochem Cytochem. 2001;49:323-332
34. Fujimaki T, Kato K, Yokoi K, Oguri M, Yoshida T, Watanabe S, Metoki N, Yoshida H, Satoh K, Aoyagi Y, Nozawa Y, Kimura G, Yamada Y. Association of genetic variants in SEMA3F, CLEC16A, LAMA3, and PCSK2 with myocardial infarction in Japanese individuals. Atherosclerosis. 2010;210:468-473
35. Li JP, Wang XB, Chen CZ, Xu X, Hong XM, Xu XP, Gao W, Huo Y. The association between paired basic amino acid cleaving enzyme 4 gene haplotype and diastolic blood pressure. Chin Med J (Engl). 2004;117:382-388
36. Ganesh SK, Tragante V, Guo W, et al CARDIOGRAM, METASTROKE; LifeLines Cohort Study. Loci influencing blood pressure identified using a cardiovascular gene-centric array. Hum Mol Genet. 2013;22:1663-1678
37. Iatan I, Dastani Z, Do R, Weissglas-Volkov D, Ruel I, Lee JC, Huertas-Vazquez A, Taskinen MR, Prat A, Seidah NG, Pajukanta P, Engert JC, Genest J. Genetic variation at the proprotein convertase subtilisin/kexin type 5 gene modulates high-density lipoprotein cholesterol levels. Circ Cardiovasc Genet. 2009;2:467-475
38. Seidah NG, Prat A. The biology and therapeutic targeting of the proprotein convertases. Nat Rev Drug Discov. 2012;11:367-383
39. Gomez D, Owens GK. Smooth muscle cell phenotypic switching in atherosclerosis. Cardiovasc Res. 2012;95:156-164
40. Suh JH, Yoon JS, Kwon JB, Kim HW, Wang YP. Identification of genomic aberrations by array comparative genomic hybridization in patients with aortic dissections. Korean J Thorac Cardiovasc Surg. 2011;44:123-130
41. Tsuji A, Sakurai K, Kiyokage E, Yamazaki T, Koide S, Toida K, Ishimura K, Matsuda Y. Secretory proprotein convertases PACE4 and PC6A are heparin-binding proteins which are localized in the extracellular matrix. Potential role of PACE4 in the activation of proproteins in the extracellular matrix. Biochim Biophys Acta. 2003;1645:95-104
42. 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
43. Newby AC. Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and nonmatrix substrates. Cardiovasc Res. 2006;69:614-624
44. Tran-Lundmark K, Tran PK, Paulsson-Berne G, Fridén V, Soininen R, Tryggvason K, Wight TN, Kinsella MG, Borén J, Hedin U. Heparan sulfate in perlecan promotes mouse atherosclerosis: Roles in lipid permeability, lipid retention, and smooth muscle cell proliferation. Circ Res. 2008;103:43-52
45. Tran PK, Tran-Lundmark K, Soininen R, Tryggvason K, Thyberg J, Hedin U. Increased intimal hyperplasia and smooth muscle cell proliferation in transgenic mice with heparan sulfate-deficient perlecan. Circ Res. 2004;94:550-558
46. Geng YJ, Libby P. Progression of atheroma: A struggle between death and procreation. Arterioscler Thromb Vasc Biol. 2002;22:1370-1380
47. Bando M, Matsuoka A, Tsuji A, Matsuda Y. The proprotein convertase PACE4 is upregulated by PDGF-BB in megakaryocytes: Gene expression of PACE4 and furin is regulated differently in Dami cells. J Biochem. 2002;132:127-134
48. Nergiz-Unal R, Rademakers T, Cosemans JM, Heemskerk JW. CD36 as a multiple-ligand signaling receptor in atherothrombosis. Cardiovasc Hematol Agents Med Chem. 2011;9:42-55
49. Lu Y, Feskens EJ, Boer JM, Imholz S, Verschuren WM, Wijmenga C, Vaarhorst A, Slagboom E, Müller M, Dollé ME. Exploring genetic determinants of plasma total cholesterol levels and their predictive value in a longitudinal study. Atherosclerosis. 2010;213:200-205
50. Olofsson PS, Söderström LA, Wågsäter D, Sheikine Y, Ocaya P, Lang F, Rabu C, Chen L, Rudling M, Aukrust P, Hedin U, Paulsson-Berne G, Sirsjö A, Hansson GK. CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice. Circulation. 2008;117:1292-1301
51. Salem MK, Vijaynagar B, Sayers RD, West K, Moore D, Robinson TG, Naylor AR, Bown MJ. Histologically unstable asymptomatic carotid plaques have altered expression of genes involved in chemokine signalling leading to localised plaque inflammation and rupture. Eur J Vasc Endovasc Surg. 2013;45:121-127