Indomethacin Prevents the Progression of Thoracic Aortic Aneurysm in Marfan Syndrome Mice

Abstract

Background: Marfan syndrome (MFS), an inherited disorder of connective tissue characterized by abnormalities in the skeletal, ocular, and cardiovascular systems, is caused by mutations in the gene for fibrillin-1 (FBN1). The high mortality in untreated patients is primarily due to aneurysm and dissection of the ascending aorta. The complex pathogenesis of MFS involves changes in transforming growth factor β (TGF-β) signaling, increased matrix metalloproteinase (MMP) expression, and fragmentation of the extracellular matrix. A number of studies have demonstrated increased counts of macrophages and T cells in the ascending aorta of persons or mouse models of MFS, but the efficacy of anti-inflammatory therapy in mouse models of MFS has not yet been assessed.

Methods: FBN1 underexpressing mgR/mgR Marfan mice were treated with oral indomethacin. Treatment was begun at the age of three weeks and continued for 8 weeks, following which the aorta of wild type as well as treated and untreated mgR/mgR mice was compared.

Results: Indomethacin treatment led to a statistically significant reduction of aortic elastin degeneration and macrophage infiltration, as well as a lessening of MMP-2, MMP-9, and MMP-12 upregulation. Additionally, indomethacin decreased both cyclooxygenases 2 (COX-2) expression and activity in the aorta of mgR/mgR mice. COX-2-mediated inflammatory infiltrate contributes to the progression of aortic aneurysm in mgR/mgR mice, providing evidence that COX-2 is a relevant therapeutic target in MFS-associated aortic aneurysmal disease.

Conclusions: COX-2 mediated inflammatory infiltration plays an important role in the pathogenesis of aortic aneurysm disease in MFS.

Key Words

Aorta - Aneurysm - Inflammatory infiltrate - Marfan syndrome

• References

• 1 von Kodolitsch Y, Robinson PN. Marfan syndrome: An update of genetics, medical and surgical management. Heart 2007; 93: 755-760
• 2 Adair-Kirk TL, Senior RM. Fragments of extracellular matrix as mediators of inflammation. Int J Biochem Cell Biol 2008; 40: 1101-1110 . 10.1016/j.biocel.2007.12.005
• 3 O'Reilly PJ, Gaggar A, Blalock JE. Interfering with extracellular matrix degradation to blunt inflammation. Curr Opin Pharmacol 2008; 8: 242-248 . 10.1016/j.coph.2008.02.003
• 4 Nataatmadja M, West M, West J, Summers K, Walker P, Nagata M. , et al. Abnormal extracellular matrix protein transport associated with increased apoptosis of vascular smooth muscle cells in Marfan syndrome and bicuspid aortic valve thoracic aortic aneurysm. Circulation 2003; 108 (suppl 1) I329-I334
• 5 Segura AM, Luna RE, Horiba K, Stetler-Stevenson WG, McAllister Jr. HA, Willerson JT. , et al. Immunohistochemistry of matrix metalloproteinases and their inhibitors in thoracic aortic aneurysms and aortic valves of patients with Marfan's syndrome. Circulation 1998; 98: II331-II337
• 6 He R, Guo DC, Sun W, Papke CL, Duraisamy S, Estrera AL. , et al. Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms, and sporadic aneurysms. J Thorac Cardiovasc Surg 2008; 136: 922-929 . 10.1016/j.jtcvs.2007.12.063
• 7 Guo G, Booms P, Halushka M, Dietz HC, Ney A, Stricker S. , et al. Induction of macrophage chemotaxis by aortic extracts of the mgR Marfan mouse model and a GxxPG-containing fibrillin-1 fragment. Circulation 2006; 114: 1855-1862.
• 8 Radonic T, de Witte P, Groenink M, de Waard V, Lutter R, van Eijk M. , et al. Inflammation aggravates disease severity in Marfan syndrome patients. PLoS ONE 2012; 7: e32963
• 9 Pereira L, Lee SY, Gayraud B, Andrikopoulos K, Shapiro SD, Bunton T. , et al. Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci USA 1999; 96: 3819–3823
• 10 Bunton TE, Biery NJ, Myers L, Gayraud B, Ramirez F, Dietz HC. Phenotypic alteration of vascular smooth muscle cells precedes elastolysis in a mouse model of Marfan Syndrome. Circ Res 2001; 88: 37-43 . 10.1161/01.RES.88.1.37
• 11 Guo G, Gehle P, Doelken S, Martin-Ventura JL, von Kodolitsch Y, Hetzer R. , et al. Induction of macrophage chemotaxis by aortic extracts from patients with Marfan syndrome is related to elastin binding protein. PLoS ONE 2011; 6: e20138
• 12 Guo G, Muñoz-García B, Ott C, Grünhagen J, Shaaban A, Pletschacher A. , et al. Antagonism of GxxPG fragments ameliorates manifestations of aortic disease in Marfan syndrome mice. Hum Mol Genet 2013; 22 (03) 433-443
• 13 Warner TD, Mitchell JA. Cyclooxygenases: New forms, new inhibitors, and lessons from the clinic. FASEB J 2004; 18: 790-804 . 10.1096/fj.03–0645rev
• 14 Chung AW, Yeung KA, Cortes SF, Sandor GG, Judge DP, Dietz HC. , et al. Endothelial dysfunction and compromised eNOS/Akt signaling in the thoracic aorta during the progression of Marfan syndrome. Br J Pharmacol 2007; 150 (08) 1075-1083
• 15 Miralles M, Wester W, Sicard GA, Thompson R, Reilly JM. Indomethacin inhibits expansion of experimental aortic aneurysms via inhibition of the COX2 isoform of cyclooxygenase. J Vasc Surg 1999; 29: 884-892 . 10.1016/S0741–5214(99)70216–8
• 16 Walton LJ, Franklin IJ, Bayston T, Brown LC, Greenhalgh RM, Taylor GW. , et al. Inhibition of prostaglandin E2 synthesis in abdominal aortic aneurysms: Implications for smooth muscle cell viability, inflammatory processes, and the expansion of abdominal aortic aneurysms. Circulation 1999; 100: 48-54
• 17 Holmes DR, Wester W, Thompson RW, Reilly JM. Prostaglandin E2 synthesis and cyclooxygenase expression in abdominal aortic aneurysms. J Vasc Surg 1997; 25: 810-815 . 10.1016/S0741–5214(97)70210–6
• 18 Chung AW, Yeung KA, Sandor GG, Judge DP, Dietz HC, van Breemen C. Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in the thoracic aortic aneurysm in Marfan syndrome. Circ Res 2007; 101: 512-522 . 10.1161/CIRCRESAHA.107.157776
• 19 Chung AW, Yang HH, Radomski MW, van Breemen C. Long-term doxycycline is more effective than atenolol to prevent thoracic aortic aneurysm in Marfan syndrome through the inhibition of matrix metalloproteinase-2 and -9. Circ Res 2008; 102 (08) e73-e85 . 10.1161/CIRCRESAHA.108.174367
• 20 Ikonomidis JS, Jones JA, Barbour JR, Stroud RE, Clark LL, Kaplan BS. , et al. Expression of matrix metalloproteinases and endogenous inhibitors within ascending aortic aneurysms of patients with Marfan syndrome. Circulation 2006; 114 (suppl 1): I365-I370
• 21 Neptune ER, Frischmeyer PA, Arking DE, Myers L, Bunton TE, Gayraud B. , et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 2003; 33: 407-411 . 10.1038/ng1116
• 22 Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys B, Cooper TK. , et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006; 312: 117-121
• 23 Holm TM, Habashi JP, Doyle JJ, Bedja D, Chen Y, van Erp C. , et al. Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science 2011; 332: 358-361
• 24 Habashi JP, Doyle JJ, Holm TM, Aziz H, Schoenhoff F, Bedja D. , et al. Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science 2011; 332: 361-365
• 25 McLoughlin D, McGuinness J, Byrne J, Terzo E, Huuskonen V, McAllister H. , et al. Pravastatin reduces Marfan aortic dilation. Circulation 2011; 124: S168-S173