Related Experiment Video
Updated: Jul 8, 2026
Murine Surgical Model of Topical Elastase Induced Descending Thoracic Aortic Aneurysm
Published on: August 24, 2019
Doxycycline delays aneurysm rupture in a mouse model of Marfan syndrome
Wanfen Xiong1, Rebecca A Knispel, Harry C Dietz
1Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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 (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.
Methods:
The 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.
Results:
MMP-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.
Conclusions:
This 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.
Insights
Doxycycline treatment significantly extended survival in Marfan syndrome (MFS) mice by inhibiting matrix metalloproteinases (MMPs) and reducing elastic fiber degradation, offering a potential therapeutic strategy for MFS-related thoracic aneurysms.
Area of Science:
- Cardiovascular Research
- Genetics and Molecular Biology
- Pharmacology
Background:
- Marfan syndrome (MFS) is a genetic disorder affecting connective tissue, primarily caused by mutations in the fibrillin-1 (FBN1) gene.
- Thoracic aortic aneurysms are a life-threatening complication of MFS, leading to premature death.
- Matrix metalloproteinases (MMPs) are implicated in aortic aneurysm pathogenesis, but their specific role in MFS requires elucidation.
Purpose of the Study:
- To investigate the role of MMPs in the pathogenesis of thoracic aneurysms in a mouse model of MFS.
- To determine if doxycycline, a broad-spectrum MMP inhibitor, can attenuate matrix degradation and improve survival in MFS mice.
Main Methods:
- Utilized fibrillin-1 under-expressing mice (mgR/mgR) as a model for MFS, characterized by spontaneous thoracic aortic rupture.
- Administered doxycycline to mgR/mgR mice and control wild-type littermates starting at postnatal day 1.
- Assessed lifespan, performed histological analysis of thoracic aortas, and conducted zymography to quantify MMP-2 and MMP-9 levels.
Main Results:
- mgR/mgR mice exhibited elevated MMP-2 and MMP-9 levels in the thoracic aorta compared to wild-type mice.
- Doxycycline treatment significantly increased the lifespan of mgR/mgR mice (132 days vs. 79 days).
- Histological analysis revealed that doxycycline reduced elastic fiber degradation and decreased MMP-2 and MMP-9 expression in treated MFS mice.
Conclusions:
- Doxycycline treatment effectively inhibits MMP-2 and MMP-9 expression, thereby reducing elastic matrix degradation in MFS mice.
- This inhibition of matrix degradation significantly delays thoracic aneurysm rupture and prolongs survival in MFS.
- The findings suggest that MMPs are key contributors to thoracic aneurysm progression in MFS, and doxycycline shows therapeutic potential for managing the disease.
