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AP-1 Oligodeoxynucleotides Reduce Aortic Elastolysis in a Murine Model of Marfan Syndrome
Rawa Arif1, Marcin Zaradzki1, Anca Remes2
1Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany.
Abstract:
Marfan syndrome is characterized by high expression of matrix metalloproteinases (MMPs) in aortic smooth muscle cells (AoSMCs) associated with medial elastolysis and aortic root aneurysm. We aimed to reduce aortic elastolysis through decrease of MMP expression with decoy oligodeoxynucleotides (dODNs) neutralizing the transcription factor activating factor-1 (AP-1). AP-1 abundance in nuclear extracts as well as MMP-2 and MMP-9 expression were significantly increased in isolated mAoSMC of mgR/mgR Marfan mice compared to wild-type cells. Exposure to AP-1 neutralizing dODNs resulted in a significant reduction of basal and interleukin-1β-stimulated MMP expression and activity in mAoSMCs. Moreover, increased migration and formation of superoxide radical anions was substantially decreased in mAoSMCs by AP-1 dODN treatment. Aortic grafts from donor Marfan mice were treated with AP-1- dODN ex vivo and implanted as infrarenal aortic interposition grafts in mgR/mgR mice. Pretreatment of aortic grafts with AP-1 dODN led to reduced elastolysis, macrophage infiltration, and MMP activity. Permeability of the endothelial monolayer was increased for dODN in mgR/mgR aortae with observed loss of tight junction proteins ZO-1 and occludin, enabling dODN to reach the tunica media. Targeting AP-1 activity offers a new potential strategy to treat the vascular phenotype associated with Marfan syndrome.
Insights
Targeting activating factor-1 (AP-1) with decoy oligodeoxynucleotides (dODNs) reduced matrix metalloproteinase (MMP) expression and aortic elastolysis in Marfan syndrome mouse models. This approach offers a potential strategy for treating vascular complications.
Area of Science:
- Vascular Biology
- Genetics
- Molecular Medicine
Background:
- Marfan syndrome is linked to elevated matrix metalloproteinases (MMPs) in aortic smooth muscle cells, causing medial elastolysis and aortic aneurysm.
- Activating factor-1 (AP-1) is a transcription factor implicated in regulating MMP expression.
Purpose of the Study:
- To investigate the efficacy of AP-1 neutralizing decoy oligodeoxynucleotides (dODNs) in reducing aortic elastolysis in Marfan syndrome.
- To explore AP-1's role in MMP expression and vascular dysfunction in Marfan syndrome.
Main Methods:
- Assessed AP-1 abundance and MMP-2/MMP-9 expression in Marfan mouse aortic smooth muscle cells (AoSMCs).
- Treated Marfan AoSMCs with AP-1 dODNs ex vivo and evaluated MMP expression, activity, migration, and superoxide anion formation.
- Pretreated Marfan aortic grafts with AP-1 dODN before implantation and assessed elastolysis, macrophage infiltration, and MMP activity.
Main Results:
- Marfan mouse AoSMCs showed increased AP-1, MMP-2, and MMP-9 expression compared to wild-type.
- AP-1 dODN treatment significantly reduced basal and IL-1β-stimulated MMP expression and activity in Marfan AoSMCs.
- dODN treatment decreased Marfan AoSMC migration and superoxide anion formation.
- Ex vivo AP-1 dODN pretreatment of aortic grafts reduced post-implantation elastolysis, macrophage infiltration, and MMP activity.
- Increased aortic permeability in Marfan mice allowed dODN penetration to the tunica media, disrupting tight junctions.
Conclusions:
- Targeting AP-1 with dODNs is a promising strategy to mitigate the vascular pathology of Marfan syndrome.
- This approach effectively reduces MMP-driven aortic elastolysis and associated complications.
