Doxycycline delays aneurysm rupture in a mouse model of Marfan syndrome

ObjectivesThoracic 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 (FBN1), a major constituent of the elastic fibers. Matrix metalloproteinases (MMPs) are important in the pathogenesis of abdominal aortic aneurysms but their precise role in MFS is not clear. Doxycycline is a nonspecific MMP inhibitor. The objective of the study was to determine whether docycycline can attenuate matrix degradation and prolong the survival of mice with MFS.MethodsThe study employed a well-characterized animal model of MFS, namely fibrillin-1 under-expressing mice (mgR/mgR mice) that die spontaneously from rupture of the thoracic aorta between 2 to 4 months of age. Mutant and wild type mice were given doxycycline in their drinking water at a concentration designed to provide 100 mg/kg/day beginning at postnatal day (PD) 1, whereas control mice were given water. Treated mice were divided into two groups. One group of animals was followed until death or for 7 months to determine lifespan. In the second group 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 6 weeks.ResultsMMP-2 and MMP-9 levels were higher in the thoracic aorta of mgR/mgR mice compared with wild type littermates. Doxycycline-treated mgR/mgR mice lived 132 ± 14.6 days (n = 16) or significantly longer than untreated mutant mice (79 ± 6.7 days, n = 30) (P < 0.01). Connective tissue staining showed that doxycycline treatment decreased elastic fiber degradation in mgR/mgR mice. Furthermore, mgR/mgR mice treated with doxycycline had lower MMP-2 and MMP-9 levels compared with untreated mgR/mgR mice.ConclusionsThis study demonstrates that doxycycline significantly delays aneurysm rupture in MFS-like mice by inhibiting expression of tissue MMP-2 and MMP-9 and thus, degradation of the elastic matrix. The results suggest that MMPs contribute to the progression of thoracic aneurysm in MFS and that doxycycline has the potential to significantly alter the course of the disease.

Clinical RelevanceAortic aneurysms are the main cardiovascular complication of Marfan syndrome (MFS) resulting in premature death. β-blockers offer some benefit but do not address the underlying cause of the progressive aortic degradation. Medical treatment that actually targets recently identified pathogenic factors leading to progressive matrix destruction could significantly impact the clinical course of the disease. A recent study using a mouse model of MFS has demonstrated that TGF- β antibodies or the angiotensin II type I receptor (AT1) antagonist losartan can both effectively rescue aneurysm progression. We have found that doxycycline, a nonspecific inhibitor of matrix metalloproteinases (MMPs), can decrease elastin degradation and prolong the lifespan of genetically engineered mice that mimic the human disease process. Based on these results, further testing may be warranted to determine if doxycycline could favorable impact the natural history of Marfan syndrome.