Aortic aneurysm is a focal and permanent dilation of the aorta and, if left untreated,
can expand progressively and increase the risk of aortic rupture and death. At present,
there is no effective pharmacologic treatment for aortic aneurysm; corrective surgery
is the only viable treatment. Therefore, a better understanding of the mechanism underlying
aortic aneurysm is required to identify potential treatments. In this issue of the
Canadian Journal of Cardiology, Yao et al.
1
report that whole body genetic loss of caspase recruitment domain and membrane-associated
guanylate kinase-like domain protein 3 (CARMA3) increases the risk of abdominal aortic
aneurysm (AAA) formation and aortic rupture in angiotensin II (Ang II)-infused mice.
Aortic dilation is caused by weakened aortic wall brought about by adverse remodelling
of the aortic structure.
2
Vascular smooth muscle cells (VSMCs) are critical cell types in the tunica media
of the aortic wall and are responsible for production of extracellular matrix (ECM)
proteins as well the contractile function that enforces the recoil of the aortic wall
during cardiac diastole.
3
Therefore, impaired function or loss of VSMCs can deteriorate the strength and integrity
of the aortic wall and cause aortic dilation and aneurysm. There are several types
of cell death that can be inflicted on the VSMCs, including necrosis, apoptosis, pyroptosis,
autophagy, and ferroptosis. In recent years, pyroptosis, a proinflammatory programmed
cell death that is distinct from apoptosis—a noninflammatory programmed cell death—has
been receiving more attention in cardiovascular diseases.
4
Pyroptosis is triggered by the activation of the NOD-like receptor 3 (NLRP3) inflammasome
and inflammatory caspases. Caspase I can cleave gasdermin D (GSDMD) into N-terminal
(GSDMD-N) and C-terminal domains. GSDMD-N then oligomerizes to form pores in the cell
membrane, allowing mature interleukin (IL)-1β and IL-18 to be released into the extracellular
space. Meanwhile, water entering through the pores causes cell swelling and lysis,
eventually resulting in cell-membrane rupture.
5
Inflammation is a major contributor to formation of AAA, and the contribution of
inflammasomes to this process has received more attention in recent years.
6
Activation of the NLRP3-caspase-1 system in human and mouse aneurysmal tissue results
in the degradation of the contractile proteins in VSMCs and can promote formation
of aneurysms.
7
- Wu D.
- Ren P.
- Zheng Y.
- et al.
NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing
3)-caspase-1 inflammasome degrades contractile proteins: implications for aortic biomechanical
dysfunction and aneurysm and dissection formation.
Arterioscler Thromb Vasc Biol. 2017; 37: 694-706
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Article info
Publication history
Published online: April 20, 2023
Accepted:
April 18,
2023
Received:
April 7,
2023
Publication stage
In Press Journal Pre-ProofFootnotes
See article by Yao et al., pages xxx-xxx of this issue.
See page 2 for disclosure information.
Identification
Copyright
© 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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- CARMA3 deficiency aggravates angiotensin II-induced abdominal aortic aneurysms development interacting between endoplasmic reticulum and mitochondriaCanadian Journal of Cardiology
- PreviewAbdominal aortic aneurysm (AAA) is life threatening and associated with vascular walls’ chronic inflammation. However, a detailed understanding of the underlying mechanisms is yet to be elucidated. CARMA3 assembles the CARMA3‐BCL10‐MALT1 (CBM) complex in inflammatory diseases and is proven to mediate angiotensin II (Ang II) response to inflammatory signals by modulating DNA damage-induced cell pyroptosis. Additionally, interaction between endoplasmic reticulum (ER) stress and mitochondrial damage is one of the main causes of cell pyroptosis.
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