Molecular basis for the development of intracranial aneurysm

Expert Review of Neurotherapeutics

Volumn 10, Issue 2, 2010, Pages 173-187

  Kataoka, Hiroharu ^a   Aoki, Tomohiro ^a  

^a NATIONAL HOSPITAL ORGANIZATION HIMEJI MEDICAL CENTER   (Japan)

Author keywords

animal model; apoptosis; gene expression profiling; genetics; inflammation; vascular remodeling

Indexed keywords

EID: 85008318789     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/ern.09.155     Document Type: Article

References (123)

1. Hop JW, Rinkel GJ, Algra A, van GJ. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke 28 (3), 660 –664 (1997).
2. Johnston SC, Selvin S, Gress DR. The burden, trends, and demographics of mortality from subarachnoid hemorrhage. Neurology 50 (5), 1413 –1418 (1998).
3. Wiebers DO, Whisnant JP, Huston J III et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 362 (9378), 103 –110 (2003).
4. Bederson JB, Awad IA, Wiebers DO et al. Recommendations for the management of patients with unruptured intracranial aneurysms: a statement for healthcare professionals from the Stroke Council of the American Heart Association. Circulation 102 (18), 2300 –2308 (2000).
5. Komotar RJ, Mocco J, Solomon RA. Guidelines for the surgical treatment of unruptured intracranial aneurysms: the first annual J. Lawrence pool memorial research symposium – controversies in the management of cerebral aneurysms. Neurosurgery 62 (1), 183 –193 (2008).
6. Juvela S. Natural history of unruptured intracranial aneurysms: risks for aneurysm formation, growth, and rupture. Acta Neurochir. Suppl. 82, 27 –30 (2002).
7. Juvela S. Prehemorrhage risk factors for fatal intracranial aneurysm rupture. Stroke 34 (8), 1852 –1857 (2003).
8. Schievink WI, Schaid DJ, Rogers HM, Piepgras DG, Michels VV. On the inheritance of intracranial aneurysms. Stroke 25 (10), 2028 –2037 (1994).
9. Schievink WI, Michels VV, Piepgras DG. Neurovascular manifestations of heritable connective tissue disorders. A review. Stroke 25 (4), 889 –903 (1994).
10. Ronkainen A, Hernesniemi J, Ryynanen M. Familial subarachnoid hemorrhage in east Finland, 1977–1990. Neurosurgery 33 (5), 787 –796 (1993).
11. Schievink WI, Schaid DJ, Michels VV, Piepgras DG. Familial aneurysmal subarachnoid hemorrhage: a community-based study. J. Neurosurg. 83 (3), 426 –429 (1995).
12. Onda H, Kasuya H, Yoneyama T et al. Genome wide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7q11. Am. J. Hum. Genet. 69 (4), 804 –819 (2001).
13. Farnham JM, Camp NJ, Neuhausen SL et al. Confirmation of chromosome 7q11 locus for predisposition to intracranial aneurysm. Hum. Genet. 114 (3), 250 –255 (2004).
14. Mineharu Y, Inoue K, Inoue S et al. Model-based linkage analyses confirm chromosome 19q13.3 as a susceptibility locus for intracranial aneurysm. Stroke 38 (4), 1174 –1178 (2007).
15. Yamada S, Utsunomiya M, Inoue K et al. Absence of linkage of familial intracranial aneurysms to 7q11 in highly aggregated Japanese families. Stroke 34 (4), 892 –900 (2003).
16. Olson JM, Vongpunsawad S, Kuivaniemi H et al. Search for intracranial aneurysm susceptibility gene(s) using Finnish families. BMC Med. Genet. 3, 7 (2002).
17. van der Voet, Olson JM, Kuivaniemi H et al. Intracranial aneurysms in Finnish families: confirmation of linkage and refinement of the interval to chromosome 19q13.3. Am. J. Hum. Genet. 74 (3), 564 –571 (2004).
18. Yamada S, Utsunomiya M, Inoue K et al. Genome-wide scan for Japanese familial intracranial aneurysms: linkage to several chromosomal regions. Circulation 110 (24), 3727 –3733 (2004).
19. Nahed BV, Seker A, Guclu B et al. Mapping a Mendelian form of intracranial aneurysm to 1p34.3-p36.13. Am. J. Hum. Genet. 76 (1), 172 –179 (2005).
20. Ruigrok YM, Wijmenga C, Rinkel GJ et al. Genomewide linkage in a large Dutch family with intracranial aneurysms: replication of 2 loci for intracranial aneurysms to chromosome 1p36.11–p36.13 and Xp22.2–p22.32. Stroke 39 (4), 1096 –1102 (2008).
21. Ozturk AK, Nahed BV, Bydon M et al. Molecular genetic analysis of two large kindreds with intracranial aneurysms demonstrates linkage to 11q24–25 and 14q23–31. Stroke 37 (4), 1021 –1027 (2006).
22. Verlaan DJ, Dube MP, St-Onge J et al. A new locus for autosomal dominant intracranial aneurysm, ANIB4, maps to chromosome 5p15.2–14.3. J. Med. Genet. 43 (6), e31 (2006).
23. Krischek B, Narita A, Akagawa H et al. Is there any evidence for linkage on chromosome 17cen in affected Japanese sib-pairs with an intracranial aneurysm? J. Hum. Genet. 51 (5), 491 –494 (2006).
24. Broderick JP, Sauerbeck LR, Foroud T et al. The Familial Intracranial Aneurysm (FIA) study protocol. BMC. Med. Genet. 6, 17 (2005).
25. Foroud T, Sauerbeck L, Brown R et al. Genome screen to detect linkage to intracranial aneurysm susceptibility genes: the Familial Intracranial Aneurysm (FIA) study. Stroke 39 (5), 1434 –1440 (2008).
26. Foroud T, Sauerbeck L, Brown R et al. Genome screen in familial intracranial aneurysm. BMC Med. Genet. 10, 3 (2009).
27. Akagawa H, Tajima A, Sakamoto Y et al. A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms. Hum. Mol. Genet. 15 (10), 1722 –1734 (2006).
28. Ruigrok YM, Seitz U, Wolterink S, Rinkel GJ, Wijmenga C, Urban Z. Association of polymorphisms and haplotypes in the elastin gene in Dutch patients with sporadic aneurysmal subarachnoid hemorrhage. Stroke 35 (9), 2064 –2068 (2004).
29. Berthelemy-Okazaki N, Zhao Y, Yang Z et al. Examination of ELN as a candidate gene in the Utah intracranial aneurysm pedigrees. Stroke 36 (6), 1283 –1284 (2005).
30. Hofer A, Hermans M, Kubassek N et al. Elastin polymorphism haplotype and intracranial aneurysms are not associated in Central Europe. Stroke 34 (5), 1207 –1211 (2003).
31. Krex D, Konig IR, Ziegler A, Schackert HK, Schackert G. Extended single nucleotide polymorphism and haplotype analysis of the elastin gene in Caucasians with intracranial aneurysms provides evidence for racially/ethnically based differences. Cerebrovasc. Dis. 18 (2), 104 –110 (2004).
32. Yoneyama T, Kasuya H, Onda H et al. Collagen type I α2 (COL1A2) is the susceptible gene for intracranial aneurysms. Stroke 35 (2), 443 –448 (2004).
33. Ruigrok YM, Rinkel GJ, van’t SR, Wolfs M, Tang S, Wijmenga C. Evidence in favor of the contribution of genes involved in the maintenance of the extracellular matrix of the arterial wall to the development of intracranial aneurysms. Hum. Mol. Genet. 15 (22), 3361 –3368 (2006).
34. Ruigrok YM, Rinkel GJ, Wijmenga C. The versican gene and the risk of intracranial aneurysms. Stroke 37 (9), 2372 –2374 (2006).
35. Inoue K, Mineharu Y, Inoue S et al. Search on chromosome 17 centromere reveals TNFRSF13B as a susceptibility gene for intracranial aneurysm: a preliminary study. Circulation 113 (16), 2002 –2010 (2006).
36. Y., Mineharu, K., Inoue, S., Inoue, et al., Association analysis of common variants of ELNNOS2AAPOE and ACE2 to intracranial aneurysm, Stroke, (2006), 37, 5, 1189-1194
37. T., Yoneyama, H., Kasuya, H., Onda, et al., Association of positional and functional candidate genes FGF1FBN2, and LOX on 5q31 with intracranial aneurysm, J. Hum. Genet., (2003), 48, 6, 309-314
38. Hofer A, Ozkan S, Hermans M et al. Mutations in the lysyl oxidase gene not associated with intracranial aneurysm in central European families. Cerebrovasc. Dis. 18 (3), 189 –193 (2004).
39. Khurana VG, Sohni YR, Mangrum WI et al. Endothelial nitric oxide synthase T-786C single nucleotide polymorphism: a putative genetic marker differentiating small versus large ruptured intracranial aneurysms. Stroke 34 (11), 2555 –2559 (2003).
40. Akagawa H, Kasuya H, Onda H et al. Influence of endothelial nitric oxide synthase T-786C single nucleotide polymorphism on aneurysm size. J. Neurosurg. 102 (1), 68 –71 (2005).
41. Khurana VG, Meissner I, Sohni YR et al. The presence of tandem endothelial nitric oxide synthase gene polymorphisms identifying brain aneurysms more prone to rupture. J. Neurosurg. 102 (3), 526 –531 (2005).
42. Krischek B, Kasuya H, Akagawa H et al. Using endothelial nitric oxide synthase gene polymorphisms to identify intracranial aneurysms more prone to rupture in Japanese patients. J. Neurosurg. 105 (5), 717 –722 (2006).
43. Krex D, Fortun S, Kuhlisch E, Schackert HK, Schackert G. The role of endothelial nitric oxide synthase (eNOS) genetic variants in European patients with intracranial aneurysms. J. Cereb. Blood Flow Metab. 26 (10), 1250 –1255 (2006).
44. Takenaka K, Sakai H, Yamakawa H et al. Polymorphism of the endoglin gene in patients with intracranial saccular aneurysms. J. Neurosurg. 90 (5), 935 –938 (1999).
45. Krex D, Ziegler A, Schackert HK, Schackert G. Lack of association between endoglin intron 7 insertion polymorphism and intracranial aneurysms in a white population: evidence of racial/ethnic differences. Stroke 32 (11), 2689 –2694 (2001).
46. Pera J, Slowik A, Dziedzic T et al. Endoglin gene insertion polymorphism not associated with aneurysmal subarachnoid hemorrhage. J. Neurosurg. 102 (5), 879 –881 (2005).
47. Peters DG, Kassam AB, Chang YF. A DNA sequence polymorphism in the endoglin gene is not associated with intracranial aneurysm or aneurysmal subarachnoid hemorrhage. Cerebrovasc. Dis. 20 (2), 96 –100 (2005).
48. Bilguvar K, Yasuno K, Niemela M et al. Susceptibility loci for intracranial aneurysm in European and Japanese populations. Nat. Genet. 40 (12), 1472 –1477 (2008).
49. Helgadottir A, Thorleifsson G, Magnusson KP et al. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat. Genet. 40 (2), 217 –224 (2008).
50. Kim I, Saunders TL, Morrison SJ. Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell 130 (3), 470 –483 (2007).
51. Matsui T, Kanai-Azuma M, Hara K et al. Redundant roles of Sox17 and Sox18 in postnatal angiogenesis in mice. J. Cell Sci. 119 (Pt 17), 3513 –3526 (2006).
52. Ronkainen A, Hernesniemi J, Tromp G. Special features of familial intracranial aneurysms: report of 215 familial aneurysms. Neurosurgery 37 (1), 43 –46 (1995).
53. Ruigrok YM, Rinkel GJ, Algra A, Raaymakers TW, Van Gijn J. Characteristics of intracranial aneurysms in patients with familial subarachnoid hemorrhage. Neurology 62 (6), 891 –894 (2004).
54. Kasuya H, Onda H, Takeshita M, Hori T, Takakura K. Clinical features of intracranial aneurysms in siblings. Neurosurgery 46 (6), 1301 –1305 (2000).
55. Wermer MJ, Rinkel GJ, van Gijn J. Repeated screening for intracranial aneurysms in familial subarachnoid hemorrhage. Stroke 34 (12), 2788 –2791 (2003).
56. Peters DG, Kassam AB, Feingold E et al. Molecular anatomy of an intracranial aneurysm: coordinated expression of genes involved in wound healing and tissue remodeling. Stroke 32 (4), 1036 –1042 (2001).
57. Shi C, Awad IA, Jafari N et al. Genomics of human intracranial aneurysm wall. Stroke 40 (4), 1252 –1261 (2009).
58. Mangrum WI, Farassati F, Kadirvel R et al. mRNA expression in rabbit experimental aneurysms: a study using gene chip microarrays. AJNR Am. J. Neuroradiol. 28 (5), 864 –869 (2007).
59. Kadirvel R, Ding YH, Dai D et al. Gene-expression profiling of experimental saccular aneurysms using deoxyribonucleic acid microarrays. AJNR Am. J. Neuroradiol. 29 (8), 1566 –1569 (2008).
60. Sadamasa N, Nozaki K, Kita-Matsuo H et al. Gene expression during the development of experimentally induced cerebral aneurysms. J. Vasc. Res. 45 (4), 343 –349 (2008).
61. Aoki T, Kataoka H, Ishibashi R, Nozaki K, Hashimoto N. Gene expression profile of the intima and media of experimentally induced cerebral aneurysms in rats by laser-microdissection and microarray techniques. Int. J. Mol. Med. 22 (5), 595 –603 (2008).
62. Hashimoto N, Handa H, Hazama F. Experimentally induced cerebral aneurysms in rats. Surg. Neurol. 10 (1), 3 –8 (1978).
63. Hashimoto N, Kim C, Kikuchi H, Kojima M, Kang Y, Hazama F. Experimental induction of cerebral aneurysms in monkeys. J. Neurosurg. 67 (6), 903 –905 (1987).
64. Hazama F, Hashimoto N. An animal model of cerebral aneurysms. Neuropathol. Appl. Neurobiol. 13 (2), 77 –90 (1987).
65. Nagata I, Handa H, Hashimoto N, Hazama F. Experimentally induced cerebral aneurysms in rats: Part VI. Hypertension. Surg. Neurol. 14 (6), 477 –479 (1980).
66. Hazama F, Kataoka H, Yamada E et al. Early changes of experimentally induced cerebral aneurysms in rats. Light-microscopic study. Am. J. Pathol. 124 (3), 399 –404 (1986).
67. Schievink WI. Intracranial aneurysms. N. Engl. J. Med. 336 (1), 28 –40 (1997).
68. Hara A, Yoshimi N, Mori H. Evidence for apoptosis in human intracranial aneurysms. Neurol. Res. 20 (2), 127 –130 (1998).
69. Kondo S, Hashimoto N, Kikuchi H, Hazama F, Nagata I, Kataoka H. Apoptosis of medial smooth muscle cells in the development of saccular cerebral aneurysms in rats. Stroke 29 (1), 181 –188 (1998).
70. Sakaki T, Kohmura E, Kishiguchi T, Yuguchi T, Yamashita T, Hayakawa T. Loss and apoptosis of smooth muscle cells in intracranial aneurysms. Studies with in situ DNA end labeling and antibody against single-stranded DNA. Acta Neurochir. (Wien.) 139 (5), 469 –474 (1997).
71. Morimoto M, Miyamoto S, Mizoguchi A, Kume N, Kita T, Hashimoto N. Mouse model of cerebral aneurysm: experimental induction by renal hypertension and local hemodynamic changes. Stroke 33 (7), 1911 –1915 (2002).
72. Libby P. Inflammation in atherosclerosis. Nature 420 (6917), 868 –874 (2002).
73. Ross R. Atherosclerosis-an inflammatory disease. N. Engl. J. Med. 340 (2), 115 –126 (1999).
74. Shimizu K, Mitchell RN, Libby P. Inflammation and cellular immune responses in abdominal aortic aneurysms. Arterioscler. Thromb. Vasc. Biol. 26 (5), 987 –994 (2006).
75. Thompson RW. Basic science of abdominal aortic aneurysms: emerging therapeutic strategies for an unresolved clinical problem. Curr. Opin. Cardiol. 11 (5), 504 –518 (1996).
76. Chyatte D, Bruno G, Desai S, Todor DR. Inflammation and intracranial aneurysms. Neurosurgery 45 (5), 1137 –1146 (1999).
77. Kataoka K, Taneda M, Asai T, Kinoshita A, Ito M, Kuroda R. Structural fragility and inflammatory response of ruptured cerebral aneurysms. A comparative study between ruptured and unruptured cerebral aneurysms. Stroke 30 (7), 1396 –1401 (1999).
78. Frosen J, Piippo A, Paetau A et al. Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: histological analysis of 24 unruptured and 42 ruptured cases. Stroke 35 (10), 2287 –2293 (2004).
79. Tulamo R, Frosen J, Junnikkala S et al. Complement activation associates with saccular cerebral artery aneurysm wall degeneration and rupture. Neurosurgery 59 (5), 1069 –1076 (2006).
80. Aoki T, Kataoka H, Morimoto M, Nozaki K, Hashimoto N. Macrophage-derived matrix metalloproteinase-2 and -9 promote the progression of cerebral aneurysms in rats. Stroke 38 (1), 162 –169 (2007).
81. Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2 -/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 394 (6696), 894 –897 (1998).
82. Koch AE, Kunkel SL, Pearce WH et al. Enhanced production of the chemotactic cytokines interleukin-8 and monocyte chemoattractant protein-1 in human abdominal aortic aneurysms. Am. J. Pathol. 142 (5), 1423 –1431 (1993).
83. Aoki T, Kataoka H, Ishibashi R, Nozaki K, Egashira K, Hashimoto N. Impact of monocyte chemoattractant protein-1 deficiency on cerebral aneurysm formation. Stroke 40 (3), 942 –951 (2009).
84. Chyatte D, Bruno G, Desai S, Todor DR. Inflammation and intracranial aneurysms. Neurosurgery 45 (5), 1137 –1146 (1999).
85. Jayaraman T, Berenstein V, Li X et al. Tumor necrosis factor α is a key modulator of inflammation in cerebral aneurysms. Neurosurgery 57 (3), 558 –564 (2005).
86. Jayaraman T, Paget A, Shin YS et al. TNF-α-mediated inflammation in cerebral aneurysms: a potential link to growth and rupture. Vasc. Health Risk Manag. 4 (4), 805 –817 (2008).
87. Libby P, Sukhova G, Lee RT, Galis ZS. Cytokines regulate vascular functions related to stability of the atherosclerotic plaque. J. Cardiovasc. Pharmacol. 25 (Suppl. 2), S9 –S12 (1995).
88. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327 (6122), 524 –526 (1987).
89. Tamura T, Jamous MA, Kitazato KT et al. Endothelial damage due to impaired nitric oxide bioavailability triggers cerebral aneurysm formation in female rats. J. Hypertens. 27 (6), 1284 –1292 (2009).
90. Jamous MA, Nagahiro S, Kitazato KT, Satomi J, Satoh K. Role of estrogen deficiency in the formation and progression of cerebral aneurysms. Part I: experimental study of the effect of oophorectomy in rats. J. Neurosurg. 103 (6), 1046 –1051 (2005).
91. Jamous MA, Nagahiro S, Kitazato KT, Tamura T, Kuwayama K, Satoh K. Role of estrogen deficiency in the formation and progression of cerebral aneurysms. Part II: experimental study of the effects of hormone replacement therapy in rats. J. Neurosurg. 103 (6), 1052 –1057 (2005).
92. Puder JJ, Freda PU, Goland RS, Wardlaw SL. Estrogen modulates the hypothalamic-pituitary-adrenal and inflammatory cytokine responses to endotoxin in women. J. Clin. Endocrinol. Metab. 86 (6), 2403 –2408 (2001).
93. Srivastava S, Weitzmann MN, Cenci S, Ross FP, Adler S, Pacifici R. Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD. J. Clin. Invest. 104 (4), 503 –513 (1999).
94. Pahl HL. Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18 (49), 6853 –6866 (1999).
95. Thurberg BL, Collins T. The nuclear factor-κ B/inhibitor of κB autoregulatory system and atherosclerosis. Curr. Opin. Lipidol. 9 (5), 387 –396 (1998).
96. de Winther MP, Kanters E, Kraal G, Hofker MH. Nuclear factor κB signaling in atherogenesis. Arterioscler. Thromb. Vasc. Biol. 25 (5), 904 –914 (2005).
97. Miyake T, Aoki M, Nakashima H et al. Prevention of abdominal aortic aneurysms by simultaneous inhibition of NFκB and ets using chimeric decoy oligonucleotides in a rabbit model. Gene Ther. 13 (8), 695 –704 (2006).
98. Nakashima H, Aoki M, Miyake T et al. Inhibition of experimental abdominal aortic aneurysm in the rat by use of decoy oligodeoxynucleotides suppressing activity of nuclear factor κB and ets transcription factors. Circulation 109 (1), 132 –138 (2004).
99. Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T. Transcriptional regulation of endothelial cell adhesion molecules: NF-κB and cytokine-inducible enhancers. FASEB J. 9 (10), 899 –909 (1995).
100. Shu HB, Agranoff AB, Nabel EG et al. Differential regulation of vascular cell adhesion molecule 1 gene expression by specific NF-κB subunits in endothelial and epithelial cells. Mol. Cell Biol. 13 (10), 6283 –6289 (1993).
101. Goebeler M, Gillitzer R, Kilian K et al. Multiple signaling pathways regulate NF-κB-dependent transcription of the monocyte chemoattractant protein-1 gene in primary endothelial cells. Blood 97 (1), 46 –55 (2001).
102. Ueda A, Okuda K, Ohno S et al. NF-κB and Sp1 regulate transcription of the human monocyte chemoattractant protein-1 gene. J. Immunol. 153 (5), 2052 –2063 (1994).
103. Aoki T, Kataoka H, Shimamura M et al. NF-κB is a key mediator of cerebral aneurysm formation. Circulation 116 (24), 2830 –2840 (2007).
104. Gonzalez CF, Cho YI, Ortega HV, Moret J. Intracranial aneurysms: flow analysis of their origin and progression. AJNR Am. J. Neuroradiol. 13 (1), 181 –188 (1992).
105. Jamous MA, Nagahiro S, Kitazato KT, Satoh K, Satomi J. Vascular corrosion casts mirroring early morphological changes that lead to the formation of saccular cerebral aneurysm: an experimental study in rats. J. Neurosurg. 102 (3), 532 –535 (2005).
106. Bhullar IS, Li YS, Miao H et al. Fluid shear stress activation of IκB kinase is integrin-dependent. J. Biol. Chem. 273 (46), 30544 –30549 (1998).
107. Hashimoto T, Meng H, Young WL. Intracranial aneurysms: links among inflammation, hemodynamics and vascular remodeling. Neurol. Res. 28 (4), 372 –380 (2006).
108. Lijnen HR. Metalloproteinases in development and progression of vascular disease. Pathophysiol. Haemost. Thromb. 33 (5–6), 275 –281 (2003).
109. Newby AC. Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol. Rev. 85 (1), 1 –31 (2005).
110. Freestone T, Turner RJ, Coady A, Higman DJ, Greenhalgh RM, Powell JT. Inflammation and matrix metalloproteinases in the enlarging abdominal aortic-aneurysm. Arterioscler. Thromb. Vasc. Biol. 15 (8), 1145 –1151 (1995).
111. Pyo R, Lee JK, Shipley JM et al. Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms. J. Clin. Invest. 105 (11), 1641 –1649 (2000).
112. Thompson RW, Holmes DR, Mertens RA et al. Production and localization of 92-kilodalton gelatinase in abdominal aortic-aneurysms - an elastolytic metalloproteinase expressed by aneurysm-infiltrating macrophages. J. Clin. Invest. 96 (1), 318 –326 (1995).
113. Bruno G, Todor R, Lewis I, Chyatte D. Vascular extracellular matrix remodeling in cerebral aneurysms. J. Neurosurg. 89 (3), 431 –440 (1998).
114. Kim SC, Singh M, Huang J et al. Matrix metalloproteinase-9 in cerebral aneurysms. Neurosurgery 41 (3), 642 –646 (1997).
115. Todor DR, Lewis I, Bruno G, Chyatte D. Identification of a serum gelatinase associated with the occurrence of cerebral aneurysms as pro-matrix metalloproteinase-2. Stroke 29 (8), 1580 –1583 (1998).
116. Punturieri A, Filippov S, Allen E et al. Regulation of elastinolytic cysteine proteinase activity in normal and cathepsin K-deficient human macrophages. J. Exp. Med. 192 (6), 789 –799 (2000).
117. Aoki T, Kataoka H, Ishibashi R, Nozaki K, Morishita R, Hashimoto N. Reduced collagen biosynthesis is the hallmark of cerebral aneurysm. Contribution of interleukin-1β and nuclear factor-κB. Arterioscler. Thromb. Vasc. Biol. 29 (7), 1080 –1086 (2009).
118. Yoshimura K, Aoki H, Ikeda Y et al. Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase. Nat. Med. 11 (12), 1330 –1338 (2005).
119. Takagi Y, Ishikawa M, Nozaki K, Yoshimura S, Hashimoto N. Increased expression of phosphorylated c-Jun amino-terminal kinase and phosphorylated c-Jun in human cerebral aneurysms: role of the c-Jun amino-terminal kinase/c-Jun pathway in apoptosis of vascular walls. Neurosurgery 51 (4), 997 –1002 (2002).
120. McCormick ML, Gavrila D, Weintraub NL. Role of oxidative stress in the pathogenesis of abdominal aortic aneurysms. Arterioscler. Thromb. Vasc. Biol. 27 (3), 461 –469 (2007).
121. Winrow VR, Winyard PG, Morris CJ, Blake DR. Free radicals in inflammation: second messengers and mediators of tissue destruction. Br. Med. Bull. 49 (3), 506 –522 (1993).
122. Fukuda S, Hashimoto N, Naritomi H et al. Prevention of rat cerebral aneurysm formation by inhibition of nitric oxide synthase. Circulation 101 (21), 2532 –2538 (2000).
123. Moriwaki T, Takagi Y, Sadamasa N, Aoki T, Nozaki K, Hashimoto N. Impaired progression of cerebral aneurysms in interleukin-1β-deficient mice. Stroke 37 (3), 900 –905 (2006).