Genetic deficiency of protein inhibitor of activated STAT3 suppresses experimental abdominal aortic aneurysms

Fu, Weilai; Liu, Haole; Wei, Panpan; Chen, Xia; Yu, Qingqing; Tian, Kangli; Li, Yankui; Liu, Enqi; Xu, Baohui; Miyata, Masaaki; Wang, Rong; Zhao, Sihai

doi:10.3389/fcvm.2023.1092555

Cited by 3 publications

(4 citation statements)

References 45 publications

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“…Experimental AAA was attenuated by PIAS3 deficiency together with decreased medial elastin disintegration, depletion of smooth muscle cells, accumulation of mural leukocytes, and angiogenesis. PIAS3 -/- animals had considerably fewer CD8 + T cells in the aortic wall than PIAS3 +/+ mice 45 . Compared with the control group, the CD8 + T cell level was higher in the AAA group 46 .…”

Section: Discussionmentioning

confidence: 81%

Predicting feature genes correlated with immune infiltration in patients with abdominal aortic aneurysm based on machine learning algorithms

Zhang,

2024

Sci Rep

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Abdominal aortic aneurysm (AAA) is a condition characterized by a pathological and progressive dilatation of the infrarenal abdominal aorta. The exploration of AAA feature genes is crucial for enhancing the prognosis of AAA patients. Microarray datasets of AAA were downloaded from the Gene Expression Omnibus database. A total of 43 upregulated differentially expressed genes (DEGs) and 32 downregulated DEGs were obtained. Function, pathway, disease, and gene set enrichment analyses were performed, in which enrichments were related to inflammation and immune response. AHR, APLNR, ITGA10 and NR2F6 were defined as feature genes via machine learning algorithms and a validation cohort, which indicated high diagnostic abilities by the receiver operating characteristic curves. The cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) method was used to quantify the proportions of immune infiltration in samples of AAA and normal tissues. We have predicted AHR, APLNR, ITGA10 and NR2F6 as feature genes of AAA. CD8 + T cells and M2 macrophages correlated with these genes may be involved in the development of AAA, which have the potential to be developed as risk predictors and immune interventions.

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Section: Discussionmentioning

confidence: 81%

Predicting feature genes correlated with immune infiltration in patients with abdominal aortic aneurysm based on machine learning algorithms

Zhang,

2024

Sci Rep

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“…Male CRP-deficient and WT control mice at 9 weeks of age were used for experiments. AAAs were induced in infrarenal aorta under sterile condition using porcine pancreatic elastase (PPE) infusion method as previously described (26)(27)(28). Briefly, mice were anesthetized by 2% isoflurane inhalation, and a laparotomy was created to expose the infrarenal aorta.…”

Section: Aaa Creation In Micementioning

confidence: 99%

“…To assess SMC retention, frozen aortic sections were sequentially stained with a goat anti-SMC a-actin polyclonal antibody (1:200, Cat#: NB300-978, Novus Biologicals, Centennial, CO, USA), a biotinylated rabbit anti-goat IgG antibody (1:400, Cat#: BA-5000, Vector Laboratories, Inc) and streptavidinperoxidase conjugate (1:200, Cat#: 016-030-084, Jackson ImmunoResearch), and staining was visualized using the AEC substrate kit (Vector Laboratories, Inc). Elastin fragmentation and SMC loss were scored as the grade I (mild) to IV (severe) using a histological grading system as reported previously (26)(27)(28)(29)(30)(31).…”

Section: Histological Analysis Of Medial Elastin Degradation and Smoo...mentioning

confidence: 99%

“…A standard biotin-streptavidin-peroxidase method was used for all immunohistochemical staining. Reagents used in this study were monoclonal antibodies against CD68 (macrophages, 1:200, clone #: FA-11, Cat#: 137002), CD4 (CD4 + T cells, 1:200, clone #: GK1.5, Cat#: 100402), CD8 (CD8 + T cells, 1:200, clone #: 53-6.7, Cat#: 100702), B220 (B cells, 1:200, clone #: RA3-6B2, Cat#: 103202) and CD31 (1:200, clone#: 390, Cat#: 102402) (all above mentioned primary antibodies from Biolegend Inc, San Diego, CA, USA), goat anti-mouse polyclonal antibodies against MMP2 (1:200, Cat#: AF1488, R&D Systems) and MMP9 (1:200, Cat#: AF909, R&D Systems), a biotinylated goat anti-rat secondary antibody (1:400, Cat#: BA-9400, Vector Laboratories, Inc) or rabbit anti-goat IgG secondary antibody (1:400, Cat#: BA-5000, Vector Laboratories, Inc), and streptavidin-peroxidase conjugate (1:200, Cat#: 016-030-084, Jackson ImmunoResearch) (27)(28)(29)(30)(31)(32). Macrophage accumulation was scored as the grade I to IV, and the densities of CD4 + T cells, CD8 + T cells, B220 + B cells and angiogenesis were quantified as the number of positively stained cells or neovessels per aortic cross section (ACS) (30).…”

Section: Immunohistochemical Staining For Leukocytes Angiogenesis And...mentioning

confidence: 99%

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C-reactive protein deficiency ameliorates experimental abdominal aortic aneurysms

Fu,

Liu,

et al. 2023

Front. Immunol.

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BackgroundC-reactive protein (CRP) levels are elevated in patients with abdominal aortic aneurysms (AAA). However, it has not been investigated whether CRP contributes to AAA pathogenesis.MethodsCRP deficient and wild type (WT) male mice were subjected to AAA induction via transient intra-aortic infusion of porcine pancreatic elastase. AAAs were monitored by in situ measurements of maximal infrarenal aortic external diameters immediately prior to and 14 days following elastase infusion. Key AAA pathologies were assessed by histochemical and immunohistochemical staining procedures. The influence of CRP deficiency on macrophage activation was evaluated in peritoneal macrophages in vitro.ResultsCRP protein levels were higher in aneurysmal than that in non-aneurysmal aortas. Aneurysmal aortic dilation was markedly suppressed in CRP deficient (aortic diameter: 1.08 ± 0.11 mm) as compared to WT (1.21 ± 0.08 mm) mice on day 14 after elastase infusion. More medial elastin was retained in CRP deficient than in WT elastase-infused mice. Macrophage accumulation was significantly less in aneurysmal aorta from CRP deficient than that from WT mice. Matrix metalloproteinase 2 expression was also attenuated in CRP deficient as compared to WT aneurysmal aortas. CRP deficiency had no recognizable influence on medial smooth muscle loss, lymphocyte accumulation, aneurysmal angiogenesis, and matrix metalloproteinase 9 expression. In in vitro assays, mRNA levels for tumor necrosis factor α and cyclooxygenase 2 were reduced in lipopolysaccharide activated peritoneal macrophages from CRP deficient as compared to wild type mice.ConclusionCRP deficiency suppressed experimental AAAs by attenuating aneurysmal elastin destruction, macrophage accumulation and matrix metalloproteinase 2 expression.

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CRP deposition in human abdominal aortic aneurysm is associated with transcriptome alterations toward aneurysmal pathogenesis: insights from in situ spatial whole transcriptomic analysis

Kim,

Seok,

Lim

et al. 2024

Front. Immunol.

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BackgroundWe investigated the effects of C-reactive protein (CRP) deposition on the vessel walls in abdominal aortic aneurysm (AAA) by analyzing spatially resolved changes in gene expression. Our aim was to elucidate the pathways that contribute to disease progression.MethodsAAA specimens from surgically resected formalin-fixed paraffin-embedded tissues were categorized into the AAA–high CRP [serum CRP ≥ 0.1 mg/dL, diffuse and strong immunohistochemistry (IHC); n = 7 (12 cores)] and AAA–low-CRP [serum CRP < 0.1 mg/dL, weak IHC; n = 3 (5 cores)] groups. Normal aorta specimens obtained during heart transplantation were used as the control group [n = 3 (6 cores)]. Spatially resolved whole transcriptomic analysis was performed, focusing on CD68-positive macrophages, CD45-positive lymphocytes, and αSMA-positive vascular smooth muscle cells.ResultsSpatial whole transcriptomic analysis revealed significant differential expression of 1,086, 1,629, and 1,281 genes between high-CRP and low-CRP groups within CD68-, CD45-, and αSMA-positive cells, respectively. Gene ontology (GO) analysis of CD68-positive macrophages identified clusters related to inflammation, apoptosis, and immune response, with signal transducer and activator of transcription 3 implicated across three processes. Notably, genes involved in blood vessel diameter maintenance were significantly downregulated in the high-CRP group. GO analysis of lymphocytes showed upregulation of leukocyte rolling and the apoptosis pathway, whereas, in smooth muscle cells, genes associated with Nuclear factor kappa B (NF-κB) signaling and c-Jun N-terminal Kinase (JNK) pathway were upregulated, and those related to blood pressure regulation were downregulated in the high-CRP group.DiscussionCRP deposition was associated with significant transcriptomic changes in macrophages, lymphocytes, and vascular smooth muscle cells in AAA, suggesting its potential role in promoting pro-inflammatory and apoptotic processes, as well as contributing to the degradation of vascular structure and elasticity.

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Genetic deficiency of protein inhibitor of activated STAT3 suppresses experimental abdominal aortic aneurysms

Cited by 3 publications

References 45 publications

Predicting feature genes correlated with immune infiltration in patients with abdominal aortic aneurysm based on machine learning algorithms

Predicting feature genes correlated with immune infiltration in patients with abdominal aortic aneurysm based on machine learning algorithms

C-reactive protein deficiency ameliorates experimental abdominal aortic aneurysms

CRP deposition in human abdominal aortic aneurysm is associated with transcriptome alterations toward aneurysmal pathogenesis: insights from in situ spatial whole transcriptomic analysis

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