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Updated: Oct 8, 2025
Murine Model of Thoracic Aortic Dissection Induced by Oral β-Aminopropionitrile and Subcutaneous Angiotensin II Infusion
Published on: May 16, 2025
AIM2 Inflammasome Activation Contributes to Aortic Dissection in a Sporadic Aortic Disease Mouse Model
Waleed Ageedi1, Chen Zhang1, William Case Frankel1
1Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
Background:
The absent in melanoma 2 (AIM2) inflammasome induces pyroptosis, tissue inflammation, and extracellular matrix destruction. We tested the hypothesis that the AIM2 inflammasome contributes to aortic aneurysm and dissection (AAD) development by promoting pyroptosis in smooth muscle cells (SMCs).
Methods:
We examined AIM2 expression in aortic tissues from patients with ascending thoracic aortic aneurysm (ATAA) and aortic dissection (ATAD) and from organ donor controls. AIM2's role in AAD development was evaluated in AIM2-deficient mice in a sporadic AAD model induced by challenging mice with a high-fat diet and angiotensin II infusion. The direct effects of dsDNA on SMC death in vitro were studied.
Results:
Western blot analyses showed that AIM2 was increased in ATAD compared to ATAA and control tissue. Immunofluorescence demonstrated increased AIM2 in SMCs and macrophages in the aortic media and adventitia of dissected tissue. Increased AIM2 abundance was associated with increased cleavage of caspase-1 and cleavage of gasdermin-D, indicating activation of pyroptosis. In a mouse model of sporadic AAD induced by high-fat diet and angiotensin II infusion, AIM2-deficient mice showed significant reduction in aortic dissection, but not aneurysm formation in all aortic segments, versus wild-type mice. Finally, treating cultured human aortic SMCs with double-stranded DNA induced AIM2 expression, caspase-1 cleavage, and gasdermin-D cleavage; these effects were reduced by silencing AIM2 and caspase-1 genes, suggesting involvement of the AIM2 inflammasome in cytosolic DNA-induced activation of SMC pyroptosis.
Conclusions:
Activation of the AIM2 inflammasome cascade contributes to aortic degeneration and dissection, in part, by activating pyroptosis.
Insights
The absent in melanoma 2 (AIM2) inflammasome promotes pyroptosis, contributing to aortic dissection. AIM2-deficient mice showed reduced aortic dissection, highlighting AIM2
Area of Science:
- Immunology
- Cardiovascular Biology
- Cellular Biology
Background:
- The absent in melanoma 2 (AIM2) inflammasome is known to induce pyroptosis, inflammation, and extracellular matrix destruction.
- Aortic aneurysm and dissection (AAD) involve complex inflammatory processes and tissue degradation.
- The specific role of the AIM2 inflammasome in AAD pathogenesis remained unclear.
Purpose of the Study:
- To investigate the hypothesis that the AIM2 inflammasome contributes to the development of aortic aneurysm and dissection (AAD).
- To determine if AIM2 promotes pyroptosis in smooth muscle cells (SMCs) within the context of AAD.
- To evaluate the therapeutic potential of targeting the AIM2 inflammasome pathway.
Main Methods:
- Examined AIM2 expression in human aortic tissues from patients with ascending thoracic aortic aneurysm (ATAA) and aortic dissection (ATAD) and controls.
- Evaluated the role of AIM2 in a mouse model of sporadic AAD using AIM2-deficient mice fed a high-fat diet and infused with angiotensin II.
- Investigated the direct effects of double-stranded DNA (dsDNA) on SMC death and pyroptosis markers in vitro.
Main Results:
- AIM2 expression and markers of pyroptosis (cleaved caspase-1, cleaved gasdermin-D) were significantly increased in human ATAD tissues.
- AIM2-deficient mice exhibited a significant reduction in aortic dissection, but not aneurysm formation, compared to wild-type mice in the AAD model.
- In vitro, dsDNA induced AIM2 expression and pyroptosis in human aortic SMCs, effects attenuated by AIM2 and caspase-1 gene silencing.
Conclusions:
- Activation of the AIM2 inflammasome cascade is implicated in aortic degeneration and dissection.
- Pyroptosis, driven by the AIM2 inflammasome, plays a partial role in the pathogenesis of AAD.
- Targeting the AIM2 inflammasome may offer a novel therapeutic strategy for preventing aortic dissection.
