Abstract 19141: Oxidative Stress Contributes to Aneurysm Progression in Marfan Syndrome
Rationale: Patients with the Marfan syndrome (MFS) typically develop aneurysms of the aortic root/ascending aorta and require prophylactic surgery to prevent possible dissection or rupture. Reactive oxygen species (ROS) are substrates of oxidative stress and are believed to participate in multiple vascular pathologies, however their role in MFS aneurysm development remains to be defined.
Objective: In the present study we investigated the mechanistic link between ROS signaling and aortic aneurysm development utilizing a Fbn1C1039G/+ mouse model of MFS.
METHODS AND RESULTS: Using dihydroethidium (DHE) staining and lucigenin chemiluminescence, we detected significantly increased oxidative stress in the Fbn1C1039G/+ mouse ascending (AS) aorta (6.5±0.43-fold, p=0.04), and also confirmed in human aortic root aneurysm surgical specimens. To prove that ROS contributes to aneurysm development, we treated Fbn1C1039G/+ and wild type (WT) littermate control mice with the NADPH-oxidase inhibitor acetovanillone (apocynin) (100mg/kg/day) in the drinking water from age 3-12 weeks. Apocynin treatment significantly reduced oxygen radicals and NADPH-oxidase activity within the AS aortic wall. Notably, apocynin-treated Fbn1C1039G/+ mice had significantly reduced AS aneurysm size (1.57±0.02 mm vs. 1.84±0.08 mm at 12wks, p=0.02) and decreased aortic wall elastin fragmentation compared to Fbn1C1039G/+ control (drinking water only). Corroborating with reduced elastin breakdown noted in apocynin-treated mice, in situ zymography revealed decreased aortic wall matrix metalloproteinase (MMP)-2 and -9 activity levels. Finally, to determine why ROS levels were increased in MFS, NADPH-oxidases (NOX 1-4) and superoxide-dismutases (SOD 1-3) were measured with qPCR. Interestingly, the antioxidants SOD 1-3 were significantly reduced in Fbn1C1039G/+ mice (SOD-1 4.7±0.31-fold, p<0.01; SOD-2 18.8±0.32-fold, p<0.01; SOD-3 48.5±0.16-fold, p<0.01).
Conclusion: Inhibition of NADPH-oxidase attenuates aneurysm formation in a Fbn1C1039G/+ Marfan mouse model via decreased MMP-activation. Mechanistically, increased oxidative stress in the MFS aortic wall might be caused by impaired antioxidant regulation in the mutant genotype.
Author Disclosures: F.C. Emrich: None. K. Penov: None. M. Arakawa: None. A.J. Pedroza: None. T.K. Koyano: None. C. Cheng: None. Y.M. Kim: None. U. Raaz: None. M. Adam: None. N. Beygui: None. A.J. Connolly: None. D.R. Merk: None. T. Noack: None. F.W. Mohr: None. M.P. Fischbein: Research Grant; Significant; AHA Grant in Aid, National Marfan Foundation Grant.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.