In vivo characterization of doxycycline-mediated protection of aortic function and structure in a mouse model of Marfan syndrome-associated aortic aneurysm

Abstract

Aortic aneurysm is the most life-threatening complication in Marfan syndrome (MFS) patients. Doxycycline, a nonselective matrix metalloproteinases inhibitor, was reported to improve the contractile function and elastic fiber structure and organization in a Marfan mouse aorta using ex vivo small chamber myography. In this study, we assessed the hypothesis that a long-term treatment with doxycycline would reduce aortic root growth, improve aortic wall elasticity as measured by pulse wave velocity, and improve the ultrastructure of elastic fiber in the mouse model of MFS. In our study, longitudinal measurements of aortic root diameters using high-resolution ultrasound imaging display significantly decreased aortic root diameters and lower pulse wave velocity in doxycycline-treated Marfan mice starting at 6 months as compared to their non-treated MFS counterparts. In addition, at the ultrastructural level, our data show that long-term doxycycline treatment corrects the irregularities of elastic fibers within the aortic wall of Marfan mice to the levels similar to those observed in control subjects. Our findings underscore the key role of matrix metalloproteinases during the progression of aortic aneurysm, and provide new insights into the potential therapeutic value of doxycycline in blocking MFS-associated aortic aneurysm.

Characterization of doxycycline-mediated inhibition of Marfan syndrome-associated aortic dilation by multiphoton microscopy

“…As a follow up study to our previous report, in the present study, we sought to quantitatively assess the anti-remodelling effects of long-term doxycycline treatment on the aortic ultrastructure of an established MFS mouse model using MPM 10 . This will compliment our recently reported comprehensive in vivo evaluation of aortic function and structure in live MFS mice subjected to a long-term treatment with doxycycline using ultrasound imaging 9 .…”

“…www.nature.com/scientificreports www.nature.com/scientificreports/ Doxycycline, a nonspecific broad spectrum MMP inhibitor, has been shown by our group and others to be more effective than the current "gold standard" β-blocker atenolol at attenuating MFS-associated aortic widening, and improving elastic fiber integrity and vascular function in the MFS mouse through its inhibition of MMP-2 and -9 7,22,23 . More recently, we have shown that long-term doxycycline treatment could also correct PWV starting after 18 weeks of treatment, a clinically relevant determinant of changes in aortic wall stiffness and elasticity, which is closely associated with disease progression 9 . Although previous reports have characterized the anti-remodelling effects of doxycycline treatment on elastic fiber integrity in the aorta of MFS mice, these data were analysed using classical histological techniques involving tissue fixation and staining which can alter native vessel morphology 5,7,8,23 .…”

“…term treatment with a sub-antibiotic dose of doxycycline, a general and nonspecific inhibitor of MMPs, was effective at reducing MMPs expression levels and improving aortic wall functional and structural parameters, while blocking the progression of aortic aneurysm in a well-established mouse model of MFS 7,8 . Furthermore, we have recently demonstrated that the beneficial effects of doxycycline on MFS aortic vessels are associated with significant improvements in pulse-wave velocity (PWV), which is a reliable index of aortic wall stiffness, and aortic wall elasticity in vivo 9 . However, the long-term effects of doxycycline treatment on aortic elastin and collagen ultrastructure have not yet been fully elucidated.…”

Aortic Dimensions, Biophysical Properties, and Plasma Biomarkers in Children and Adults with Marfan or Loeys-Dietz Syndrome

“…49 In the mouse model of MFS, we have previously shown that doxycycline, an antibiotic and a general inhibitor of MMPs, could correct aortic elastin fibre structure and organization and was more effective than atenolol in preventing thoracic aortic aneurysm. 50,51 Another study in our laboratory reported that drug therapy with losartan and doxycycline completely suppressed aneurysm formation in MFS mice, improved elastic fibre organization, downregulated MMP-2/-9 and TGF-b1 expression, and normalized aortic contractile and relaxation function to control values. 52 Although the implication of the findings in this study is to treat these patients with MMP inhibitors, the unsuccessful results of clinical trials of ARBs have shown that there needs to be caution in extrapolating animal model results to humans.…”

Effect of Doxycycline on Survival in Abdominal Aortic Aneurysms in a Mouse Model

“…Depending on the serum concentration, a reduction in aneurysm growth of 33–66% was observed in the mouse model [ 14 ]. In a recently published experimental study on the development of aortic aneurysms in Marfan syndrome, the therapeutic efficacy of doxycycline was confirmed [ 19 ].…”