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Doxycycline Delays Aneurysm Rupture In Marfan Syndrome

Wanfen Xiong¹, Rebecca A. Knispel¹, Francesco Ramirez², Harry C. Dietz³, Bernard T. Baxter.^1
1University of Nebraska Medical Center, Omaha, NE; ²Child Health Institute of New Jersey, UMDNJ-Robert W. Johnson Medical School, New Brunswick, NJ; ³Johns Hopkins University School of Medicine, Baltimore, MD.

OBJECTIVES: Thoracic aneurysms are the main cardiovascular complication of Marfan syndrome (MFS) resulting in premature death. MFS has been associated with mutations of the gene encoding fibrillin-1, a constituent of the elastin fiber. Matrix metalloproteinases (MMPs) are important in the pathogenesis of abdominal aortic aneurysms but there precise role in MFS is not clear. Recent in vitro studies have indicated that microfibril proteolysis also promotes macrophage chemotaxis and MMP production. Doxycycline is a nonspecific MMP inhibitor. The objective of the study is to determine whether docycycline can attenuate matrix degradation and prolong the survival of mice with MFS.

METHODS: A well-characterized murine model of MFS, fbn1mgR/mgR (fibrillin-1 under-expressing mice) was used. In these mice, death typically occurs spontaneously from rupture of the thoracic aorta between the age of 2 and 6 months. Fbn1mgR/mgR mice and wild type littermates were given doxycycline in their drinking water at a concentration designed to provide 100 mg/kg/day beginning at postnatal day (PD) 1. Control mice were given water. Treated mice were divided into two groups. One group was followed until death or for 6 months to determine lifespan. In a second set of mice, the ascending thoracic aortas were collected for histological analysis (H&E staining, Trichrome staining) and zymography for examining MMP-2 and MMP-9 levels at six weeks.

RESULTS: MMP-2 and MMP-9 levels were higher in the thoracic aorta of fbn1mgR/mgR mice compared to controls without MFS. Doxycycline treated fbn1mgR/mgR mice lived 132 ± 14.6 days (n=16) which was significantly longer than untreated mice (79 ± 6.7 days, n=30) (p<0.01). Connective tissue staining showed that doxycycline treatment decreased elastic fiber degradation in fbn1mgR/mgR mice. Furthermore, fbn1mgR/mgR mice treated with doxycycline had lower MMP-2 and MMP-9 levels compared to untreated fbn1mgR/mgR mice.

CONCLUSIONS: This study demonstrates that doxycycline significantly delays aneurysm rupture, while reducing elastin degradation and tissue MMP-2 and MMP-9. The results suggest that MMPs play an important role in MFS and that doxycycline has the potential to significantly alter the course of the disease.