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Regnase-1 overexpression as a therapeutic approach of Marfan syndrome

Rupture or dissection of thoracic aortic aneurysms is still the leading cause of death for patients diagnosed with Marfan syndrome. Inflammation and matrix digestion regulated by matrix metalloproteases (MMPs) play a major role in the pathological remodeling of the aortic media. Regnase-1 is an endo...

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Main Authors: Noormalal, Marie (Author) , Schmiedel, Nesrin (Author) , Bozoglu, Tarik (Author) , Matzen, Andrea (Author) , Hille, Susanne (Author) , Basha, Dima Ibrahim (Author) , Vijaya Shetty, Prithviraj Manohar (Author) , Wolf, Anja (Author) , Zaradzki, Marcin (Author) , Arif, Rawa (Author) , Pühler, Thomas (Author) , Lutter, Georg (Author) , Wagner, Andreas H. (Author) , Kupatt, Christian (Author) , Frank, Derk (Author) , Frey, Norbert (Author) , Remes, Anca (Author) , Müller, Oliver J. (Author)
Format: Article (Journal)
Language:English
Published: 14 Mar 2024
In: Molecular therapy. Methods & clinical development
Year: 2024, Volume: 32, Issue: 1, Pages: 1-11
ISSN:2329-0501
DOI:10.1016/j.omtm.2023.101163
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.omtm.2023.101163
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2329050123002024
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Author Notes:Marie Noormalal, Nesrin Schmiedel, Tarik Bozoglu, Andrea Matzen, Susanne Hille, Dima Ibrahim Basha, Prithviraj Manohar Vijaya Shetty, Anja Wolf, Marcin Zaradzki, Rawa Arif, Thomas Pühler, Georg Lutter, Andreas H. Wagner, Christian Kupatt, Derk Frank, Norbert Frey, Anca Remes, and Oliver J. Müller
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Summary:Rupture or dissection of thoracic aortic aneurysms is still the leading cause of death for patients diagnosed with Marfan syndrome. Inflammation and matrix digestion regulated by matrix metalloproteases (MMPs) play a major role in the pathological remodeling of the aortic media. Regnase-1 is an endoribonuclease shown to cleave the mRNA of proinflammatory cytokines, such as interleukin-6. Considering the major anti-inflammatory effects of regnase-1, here, we aimed to determine whether adeno-associated virus (AAV)-mediated vascular overexpression of the protein could provide protection from the development and progression of aortic aneurysms in Marfan syndrome. The overexpression of regnase-1 resulted in a marked decrease in inflammatory parameters and elastin degradation in aortic smooth muscle cells in vitro. Intravenous injection of a vascular-targeted AAV vector resulted in the efficient transduction of the aortic wall and overexpression of regnase-1 in a murine model of Marfan syndrome, associated with lower circulating levels of proinflammatory cytokines and decreased MMP expression and activity. Regnase-1 overexpression strongly improved elastin architecture in the media and reduced aortic diameter at distinct locations. Therefore, AAV-mediated regnase-1 overexpression may represent a novel gene therapy approach for inhibiting aortic aneurysms in Marfan syndrome.
Item Description:Gesehen am 12.08.2024
Physical Description:Online Resource
ISSN:2329-0501
DOI:10.1016/j.omtm.2023.101163

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