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FAM3A Reshapes Vascular Smooth Muscle Cell Fate Specification in Abdominal Aortic Aneurysm by Regulating KLF4 Ubiquitination

ABSTRACT: Vascular smooth muscle cell (VSMC) differentiation reprogramming plays an essential role in abdominal aortic aneurysm (AAA). However, the underlying mechanisms are still indistinct. FAM3A (family with sequence similarity 3, member A) is a newly identified metabolism regulator. We examined FAM3A expression and the downstream pathways affected by FAM3A in AAA, and how FAM3A regulated VSMC differentiation. We found that overexpression or supplement of FAM3A significantly attenuated the progression of AAA, manifested by maintenance of VSMC well-differentiation state and inhibition of VSMC transformation towards macrophage-, chondrocyte-, osteogenic-, mesenchymal-, and fibroblast-like cell subpopulations. Importantly, FAM3A induced a decrease in Krüppel-like factor 4 (KLF4) phosphorylation (Ser254) level, leading to its ubiquitination and a weakened nuclear localization. Our findings identify FAM3A as a novel VSMC fate-shaping regulator in AAA and unveil the underpinning mechanism associated with KLF4 ubiquitination and stability, which could develop new strategies based on FAM3A to restore VSMC homeostasis in AAA.

ORGANISM(S): Mus musculus

PROVIDER: GSE230163 | GEO | 2023/04/23

REPOSITORIES: GEO

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2021-05-21 | PXD024162 | Pride

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2021-11-01 | GSE186865 | GEO

PRDM16 Deficiency in Vascular Smooth Muscle Cells Aggravates Abdominal Aortic Aneurysm

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2015-06-30 | E-GEOD-57691 | biostudies-arrayexpress

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Project description:Abdominal Aortic Aneurysm (AAA) is a prevalent life-threatening disease, where aortic wall degradation is mediated by accumulated immune cells. Though cytokines regulate inflammation within the aorta, their contribution to AAA via distant alterations, particularly in the control of hematopoietic stem cell (HSC) differentiation remains poorly defined. Here we report a pathogenic role for the interleukin-27 receptor (IL-27R) in AAA as genetic ablation of IL-27R protects mice from the disease development, where the mitigation of AAA is associated with a blunted accumulation of myeloid cells in the aorta due to the attenuation of Ang II-induced HSC expansion. The loss of IL-27R engages transcriptional programs that promote HSCs quiescence and suppresses differentiation decreasing mature myeloid cell production and accumulation in the aorta. Our studies illuminate how a prominent vascular disease can be distantly driven by cytokine dependent regulation of bone marrow precursors.

2019-10-14 | GSE129881 | GEO

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2023-09-10 | GSE242508 | GEO

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Involvement of B cells, immunoglobulins, and Syk in the pathogenesis of abdominal aortic aneurysm I

Project description:Background—Abdominal aortic aneurysm (AAA) is a potentially life-threatening disease that is common in older individuals. Currently, therapeutic options are limited to surgical interventions. Although it has long been known that AAA tissue is enriched in B cells and immunoglobulins, their involvement in AAA pathogenesis remains controversial. Methods and Results— We investigated the role of B cells and immunoglobulins in a murine model of AAA, induced with a periaortic application of CaCl2, and in human AAA. Both human and mouse AAA tissue showed B cell infiltration. Mouse AAA tissue showed deposition of IgG and activation of Syk, a key molecule in B cell activation and immunoglobulin function, which were localized to infiltrating cells including B cells and macrophages. B cell-deficient muMT mice showed suppression of AAA development that was associated with reduced activation of Syk and less expression of Mmp9. Administration of exogenous immunoglobulins restored the blunted Syk activation and AAA development in muMT mice. Additionally, exogenous immunoglobulins induced IL-6 and MMP9 secretions in human AAA tissue cultures. Furthermore, administration of R788, a specific Syk inhibitor, suppressed AAA expansion, reduced inflammatory response, and reduced immunoglobulin deposition in AAA tissue. Conclusions—From these results, we concluded that B cells and immunoglobulins participated in AAA pathogenesis by promoting inflammatory and tissue destructive activities. Finally, we identified Syk as a potential therapeutic target.

2018-04-25 | GSE109638 | GEO

Involvement of B cells, immunoglobulins, and Syk in the pathogenesis of abdominal aortic aneurysm II

2018-04-25 | GSE109639 | GEO

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