Abstract
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. 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. 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. COX-2 mediated inflammatory infiltration plays an important role in the pathogenesis of aortic aneurysm disease in MFS.
Highlights
Marfan syndrome (MFS) is a hereditary connective tissue disorder caused by mutations in fibrillin-1 gene (FBN1)
We demonstrated that the nonsteroidal anti-inflammatory drug indomethacin significantly improved elastin integrity and reduced the numbers of macrophages in the aortic adventitia of mgR/mgR mice, which coincided with decreased matrix metalloproteinase (MMP)-2, Ϫ9, and Ϫ12 expression
Based on our previous and recent studies, we speculate that macrophage infiltration observed in the aortic wall of mgR/mgR Marfan mice participates in a kind of vicious cycle, in which matrix fragments induce deleterious effects, including upregulation of MMP activity and macrophage infiltration, which in turn reinforces the pathological processes associated with matrix degradation and defects in TGF- sequestration [7,11,12]
Summary
Marfan syndrome (MFS) is a hereditary connective tissue disorder caused by mutations in fibrillin-1 gene (FBN1). The most life threatening symptom of MFS is thoracic aortic aneurysm (TAA) [1] Multiple factors such as haploinsufficiency, FBN1 proteolysis, abnormal TGF- signaling, increased matrix metalloproteinase (MMP) expression, and changes in cell-matrix interaction contribute to the complex pathogenesis of this disorder. 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. 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-
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