Genetic and Pharmacological Disruption of Interleukin-1α Leads to Augmented Murine Aortic Aneurysm

Salmon, Morgan; Hawkins, Robert B.; Dahl, Jolian; Scott, Erik R.; Johnston, William F.; Ailawadi, Gorav

doi:10.1016/j.avsg.2022.05.024

Cited by 5 publications

(6 citation statements)

References 37 publications

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“…Interestingly, the levels of IL-1α and the tissue inhibitor of metalloproteinases 1 (TIMP1) were found to be significantly lower in the WT mice plasma. The suppression or genetic elimination of IL-1α or TIMP1 has been associated with the progression of AAA 26, 27 .…”

Section: Resultsmentioning

confidence: 99%

Thymidine Phosphorylase Promotes the Formation of Abdominal Aortic Aneurysm in Mice Fed a Western Diet

Hong,

Yue,

Cai

et al. 2024

Preprint

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AimsThe precise molecular drivers of abdominal aortic aneurysm (AAA) remain unclear. Thymidine phosphorylase (TYMP) contributes to increased platelet activation, thrombosis, and inflammation, all of which are key factors in AAA development. Additionally, TYMP suppresses the proliferation of vascular smooth muscle cells (VSMCs), which are central to the development and progression of AAA. We hypothesize that TYMP plays a key role in AAA development.Methods and ResultsWe conducted a histological study using human AAA samples and normal abdominal aortas, revealing heightened levels of TYMP in human AAA vessel walls. To validate this observation, we utilized an Ang II perfusion-induced AAA model in wild-type C57BL/6J (WT) andTymp−/−mice, feeding them a Western diet (TD.88137) starting from 4 weeks of age. We found thatTymp−/−mice were protected from Ang II perfusion-induced AAA formation. Furthermore, by using TYMP-expressing VSMCs as well as primarily cultured VSMCs from WT andTymp−/−mice, we elucidated the essential role of TYMP in regulating MMP2 expression and activation. TYMP deficiency or inhibition by tipiracil, a selective TYMP inhibitor, led to reduced MMP2 production, release, and activation in VSMCs. Additionally, TYMP was found to promote pro-inflammatory cytokine expression systemically, and its absence attenuates TNF-α-stimulated activation of MMP2 and AKT. By co-culturing VSMCs and platelets, we observed that TYMP-deficient platelets had a reduced inhibitory effect on VSMC proliferation compared to WT platelets. Moreover, TYMP appeared to enhance the expression of activated TGFβ1 in cultured VSMCs in vitro and in human AAA vessel walls in vivo. TYMP also boosted the activation of thrombospondin-1 type 1 repeat domain-enhanced TGFβ1 signaling, resulting in increased connective tissue growth factor production.ConclusionOur findings collectively demonstrated that TYMP serves as a novel regulatory force in vascular biology, exerting influence over VSMC functionality and inflammatory responses that promote the development of AAA.Translational PerspectiveThymidine phosphorylase (TYMP) is increased in the vessel walls of patients with abdominal aortic aneurysm (AAA), and TYMP deficiency in mice reduces the incidence of AAA, suggesting that TYMP plays a crucial role in AAA development. This could be attributed to TYMP’s role in enhancing systemic inflammation and thrombosis, inhibiting vascular smooth muscle cell function, increasing the activation of matrix metalloproteinase and AKT, as well as enhancing the expression of TGFβ1 and connective tissue growth factor. Tipiracil is an FDA-approved drug known to inhibit TYMP-enhanced thrombosis. Targeting TYMP with tipiracil could represent a promising new therapeutic strategy for AAA development.

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Section: Resultsmentioning

confidence: 99%

Thymidine Phosphorylase Promotes the Formation of Abdominal Aortic Aneurysm in Mice Fed a Western Diet

Hong,

Yue,

Cai

et al. 2024

Preprint

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“…It was also demonstrated that treatment with an anti-IL-1α neutralizing antibody inhibited AAA formation. Alternatively, another study using the elastase model of AAA observed that IL-1α deficient C57BL/6 mice had significantly larger AAA diameters compared to the wild-type controls 54 . Furthermore, administration of an anti-IL-1α neutralizing antibody exacerbated AAA formation in the study.…”

Section: Discussionmentioning

confidence: 99%

A highly selective mPGES-1 inhibitor to block abdominal aortic aneurysm progression in the angiotensin mouse model

Weaver,

Stewart,

Ding

et al. 2024

Sci Rep

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Abdominal aortic aneurysm (AAA) is a deadly, permanent ballooning of the aortic artery. Pharmacological and genetic studies have pointed to multiple proteins, including microsomal prostaglandin E2 synthase-1 (mPGES-1), as potentially promising targets. However, it remains unknown whether administration of an mPGES-1 inhibitor can effectively attenuate AAA progression in animal models. There are still no FDA-approved pharmacological treatments for AAA. Current research stresses the importance of both anti-inflammatory drug targets and rigor of translatability. Notably, mPGES-1 is an inducible enzyme responsible for overproduction of prostaglandin E2 (PGE2)—a well-known principal pro-inflammatory prostanoid. Here we demonstrate for the first time that a highly selective mPGES-1 inhibitor (UK4b) can completely block further growth of AAA in the ApoE−/− angiotensin (Ang)II mouse model. Our findings show promise for the use of a mPGES-1 inhibitor like UK4b as interventional treatment of AAA and its potential translation into the clinical setting.

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“…Both IL-1α and IL-1β are believed to be key mediators in this response. IL-1α’s function depends on its sub-cellular location, regulating normal gene expression when expressed within the cytosol during homeostasis [ 48 ]. However, in the presence of cell death, passive leakage of cytosolic IL-1α may occur.…”

Section: Introductionmentioning

confidence: 99%

“…Unlike IL-1β which has been extensively studied, little is known about the role of IL-Iα in AAA disease. One recent study demonstrated that IL-1α may help to attenuate AAA as IL-1α knockout AAA murine models were demonstrated to have larger AAA size compared to controls [ 48 ]. IL-1α knockout was also demonstrated to result in increased elastin breaks, increased levels of inflammatory macrophages and neutrophils, and increased MMPs [ 48 ].…”

Section: Introductionmentioning

confidence: 99%

“…One recent study demonstrated that IL-1α may help to attenuate AAA as IL-1α knockout AAA murine models were demonstrated to have larger AAA size compared to controls [ 48 ]. IL-1α knockout was also demonstrated to result in increased elastin breaks, increased levels of inflammatory macrophages and neutrophils, and increased MMPs [ 48 ]. The results of this study show that IL-1α and IL-1β may play separate, rather than overlapping roles, in AAA disease and that further studies specifically evaluating the role IL-1α in AAA disease are necessary [ 48 ].…”

Section: Introductionmentioning

confidence: 99%

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IL-1 in Abdominal Aortic Aneurysms

Millar

Nasser

Ailawadi

et al. 2023

Journal of Cellular Immunology

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Abdominal Aortic Aneurysms (AAA) remain a clinically devastating disease with no effective medical treatment therapy. AAAs are characterized by immune cell infiltration, smooth muscle cell apoptosis, and extracellular matrix degradation. Interleukin-1 (IL-1) has been shown to play role in AAA associated inflammation through immune cell recruitment and activation, endothelial dysfunction, production of reactive oxygen species (ROS), and regulation of transcription factors of additional inflammatory mediators. In this review, we will discuss the principles of IL-1 signaling, its role in AAA specific inflammation, and regulators of IL-1 signaling. Additionally, we will discuss the influence of genetic and pharmacological inhibitors of IL-1 on experimental AAAs. Evidence suggests that IL-1 may prove to be a potential therapeutic target in the management of AAA disease.

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Genetic and Pharmacological Disruption of Interleukin-1α Leads to Augmented Murine Aortic Aneurysm

Cited by 5 publications

References 37 publications

Thymidine Phosphorylase Promotes the Formation of Abdominal Aortic Aneurysm in Mice Fed a Western Diet

Thymidine Phosphorylase Promotes the Formation of Abdominal Aortic Aneurysm in Mice Fed a Western Diet

A highly selective mPGES-1 inhibitor to block abdominal aortic aneurysm progression in the angiotensin mouse model

IL-1 in Abdominal Aortic Aneurysms

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