Nettersheim, Felix Sebastian, Lemties, Julian, Braumann, Simon, Geissen, Simon, Bokredenghel, Senai, Nies, Richard, Hof, Alexander ORCID: 0000-0001-6554-8892, Winkels, Holger, Freeman, Bruce A., Klinke, Anna, Rudolph, Volker, Baldus, Stephan, Mehrkens, Dennis ORCID: 0000-0002-8578-0290, Mollenhauer, Martin ORCID: 0000-0002-3220-9269 and Adam, Matti (2022). Nitro-oleic acid reduces thoracic aortic aneurysm progression in a mouse model of Marfan syndrome. Cardiovasc. Res., 118 (9). S. 2211 - 2226. OXFORD: OXFORD UNIV PRESS. ISSN 1755-3245

Full text not available from this repository.

Abstract

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 extracellutar 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 (Fbn1(C1041G+)) 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 etastin fragmentation by matrix metattoproteinase 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 Fbn1(C1041G/+) 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. [GRAPHICS] .

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Nettersheim, Felix SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lemties, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braumann, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geissen, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bokredenghel, SenaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nies, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hof, AlexanderUNSPECIFIEDorcid.org/0000-0001-6554-8892UNSPECIFIED
Winkels, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Freeman, Bruce A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klinke, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rudolph, VolkerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baldus, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mehrkens, DennisUNSPECIFIEDorcid.org/0000-0002-8578-0290UNSPECIFIED
Mollenhauer, MartinUNSPECIFIEDorcid.org/0000-0002-3220-9269UNSPECIFIED
Adam, MattiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-679430
DOI: 10.1093/cvr/cvab256
Journal or Publication Title: Cardiovasc. Res.
Volume: 118
Number: 9
Page Range: S. 2211 - 2226
Date: 2022
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1755-3245
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CONJUGATED LINOLEIC-ACID; NITRATED FATTY-ACIDS; MURINE MODEL; ANGIOTENSIN-II; ACTIVATION; CONTRIBUTES; DILATATION; MICE; GENERATION; PROTECTSMultiple languages
Cardiac & Cardiovascular SystemsMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/67943

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item