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Porcine Model of Infrarenal Abdominal Aortic Aneurysm
Published on: November 21, 2019
Targeting Interleukin-1β Protects from Aortic Aneurysms Induced by Disrupted Transforming Growth Factor β Signaling
Francesco Da Ros1, Raimondo Carnevale2, Giuseppe Cifelli2
1Department of Molecular Medicine, University of Padova, Padua 35131, Italy; Department of Molecular Medicine, "Sapienza" University of Rome, 00161 Rome, Italy.
Abstract:
Aortic aneurysms are life-threatening conditions with effective treatments mainly limited to emergency surgery or trans-arterial endovascular stent grafts, thus calling for the identification of specific molecular targets. Genetic studies have highlighted controversial roles of transforming growth factor β (TGF-β) signaling in aneurysm development. Here, we report on aneurysms developing in adult mice after smooth muscle cell (SMC)-specific inactivation of Smad4, an intracellular transducer of TGF-β. The results revealed that Smad4 inhibition activated interleukin-1β (IL-1β) in SMCs. This danger signal later recruited innate immunity in the adventitia through chemokine (C-C motif) ligand 2 (CCL2) and modified the mechanical properties of the aortic wall, thus favoring vessel dilation. SMC-specific Smad4 deletion in Il1r1- or Ccr2-null mice resulted in milder aortic pathology. A chronic treatment with anti-IL-1β antibody effectively hampered aneurysm development. These findings identify a mechanistic target for controlling the progression of aneurysms with compromised TGF-β signaling, such as those driven by SMAD4 mutations.
Insights
Transforming growth factor β (TGF-β) signaling impacts aortic aneurysms. Smad4 inactivation in smooth muscle cells activates interleukin-1β (IL-1β), promoting vessel dilation and suggesting IL-1β as a therapeutic target.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Immunology
Background:
- Aortic aneurysms require novel molecular targets beyond emergency surgery.
- Transforming growth factor β (TGF-β) signaling has a complex, debated role in aneurysm pathogenesis.
- Smooth muscle cell (SMC)-specific Smad4 deficiency is investigated for its role in aneurysm development.
Purpose of the Study:
- To elucidate the role of Smad4, an intracellular TGF-β transducer, in SMCs during aortic aneurysm formation.
- To identify downstream molecular pathways activated by Smad4 inactivation in aortic SMCs.
- To explore potential therapeutic strategies targeting identified pathways for aneurysm treatment.
Main Methods:
- Induction of aortic aneurysms in adult mice via SMC-specific Smad4 inactivation.
- Analysis of inflammatory mediator activation, including interleukin-1β (IL-1β), in SMCs.
- Investigation of immune cell recruitment using chemokine (C-C motif) ligand 2 (CCL2) and receptor (CCR2) pathways.
- Assessment of aortic wall mechanical properties and vessel dilation.
- Evaluation of therapeutic efficacy using anti-IL-1β antibody treatment.
- Studies in genetically modified mice lacking IL-1β receptor (Il1r1) or CCR2 (Ccr2).
Main Results:
- SMC-specific Smad4 inactivation triggered IL-1β activation within SMCs.
- This IL-1β signal promoted adventitial innate immune cell recruitment via CCL2.
- These inflammatory changes altered aortic wall mechanics, leading to vessel dilation.
- Aneurysm development was attenuated in Il1r1- or Ccr2-null mice.
- Chronic anti-IL-1β antibody treatment significantly inhibited aneurysm progression.
Conclusions:
- SMC Smad4 deficiency initiates a pro-aneurysmal cascade involving IL-1β activation and immune cell infiltration.
- The IL-1β/CCL2/CCR2 axis is crucial for aneurysm progression driven by compromised TGF-β signaling.
- Targeting IL-1β offers a promising therapeutic avenue for aortic aneurysms, particularly those associated with SMAD4 mutations.
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