Nitro-oleic acid reduces thoracic aortic aneurysm progression in a mouse model of Marfan syndrome
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Updated: Oct 26, 2025
Murine Model of Thoracic Aortic Dissection Induced by Oral β-Aminopropionitrile and Subcutaneous Angiotensin II Infusion
Published on: May 16, 2025
Felix Sebastian Nettersheim1,2, Julian Lemties1,2, Simon Braumann1,2
1Department of Cardiology, University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
Aims:
Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene. It is associated with formation of thoracic aortic aneurysms that can potentially be a life-threatening condition due to aortic rupture or dissection. Excessive non-canonical transforming growth factor beta signalling, mediated by activation of extracellular signal-regulated kinases 1/2 (ERK1/2), as well as inducible nitric oxide synthase (NOS2)-dependent nitric oxide production, have been identified to drive aortic pathology in MFS through induction of elastin fragmentation and smooth muscle cell apoptosis. Despite promising results in animal studies, specific pharmacological interventions approved for clinical use in patients with MFS-related aortic disease are rare. Nitro-oleic acid (NO2-OA) is an endogenously generated signalling modulator, which is available as an oral compound and has been shown to inhibit ERK1/2 activation and NOS2 expression in different disease models, thereby exerting promising therapeutic effects. In this study, we investigated whether NO2-OA decreases aortic dilation in MFS.
Methods And Results:
Eight-week-old MFS (Fbn1C1041G/+) mice were treated with NO2-OA or vehicle for 4 weeks via subcutaneously implanted osmotic minipumps. Echocardiography indicated progressive ascending aortic dilation and wall stiffening in MFS mice, which was significantly attenuated by NO2-OA treatment. This protective effect was mediated by inhibition of aortic ERK1/2, Smad2 as well as nuclear factor kappa B overactivation and consequent attenuation of elastin fragmentation by matrix metalloproteinase 2, apoptosis, and collagen deposition. Critically, the therapeutic efficacy of NO2-OA in MFS was further emphasized by demonstrating its capability to reduce lethal aortic complications in Fbn1C1041G/+ mice challenged with Angiotensin II.
Conclusion:
NO2-OA distinctly attenuates progression of aortic dilation in MFS via modulation of well-established disease-mediating pathways, thereby meriting further investigation into its application as a therapeutic agent for the treatment of this condition.
Insights
Nitro-oleic acid (NO2-OA) treatment significantly reduced aortic dilation in Marfan syndrome (MFS) mouse models. This finding highlights NO2-OA as a potential therapeutic for MFS aortic disease.
Area of Science:
- Cardiovascular Research
- Genetics and Disease Mechanisms
- Pharmacology and Therapeutics
Background:
- Marfan syndrome (MFS) is a genetic connective tissue disorder characterized by thoracic aortic aneurysms, a life-threatening complication.
- Pathological mechanisms in MFS include excessive transforming growth factor beta signaling, leading to aortic wall degradation and smooth muscle cell apoptosis.
- Current pharmacological options for MFS-related aortic disease are limited, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the efficacy of nitro-oleic acid (NO2-OA) in attenuating aortic dilation in a mouse model of Marfan syndrome.
- To elucidate the molecular pathways targeted by NO2-OA in mitigating MFS-associated aortic pathology.
Main Methods:
- Marfan syndrome (Fbn1C1041G/+) mice were treated with NO2-OA or vehicle for four weeks.
- Echocardiography was used to assess aortic dimensions and stiffness.
- Aortic tissue analysis was performed to evaluate molecular changes, including signaling pathway activation, elastin fragmentation, and apoptosis.
Main Results:
- NO2-OA treatment significantly attenuated ascending aortic dilation and wall stiffening in MFS mice.
- The protective effects were associated with the inhibition of ERK1/2, Smad2, and nuclear factor kappa B signaling pathways.
- NO2-OA treatment reduced elastin fragmentation, matrix metalloproteinase 2 activity, apoptosis, and collagen deposition in the aortic wall.
- NO2-OA administration decreased lethal aortic complications in MFS mice challenged with Angiotensin II.
Conclusions:
- Nitro-oleic acid (NO2-OA) effectively reduces aortic dilation progression in Marfan syndrome.
- NO2-OA modulates key disease-mediating pathways, suggesting its potential as a therapeutic agent for MFS aortic disease.
- Further investigation into NO2-OA's clinical application for Marfan syndrome is warranted.
