STAT3 Activation Correlates with Adventitial Neutrophil Infiltration in Human Aortic Dissection

Yoshida, Shohei; Yamamoto, Masato; Aoki, Hiroki; Fukuda, Hayato; Akasu, Koji; Takagi, Kazuyoshi; Shojima, Takahiro; Akashi, Hidetoshi; Tanaka, Hiroyuki

doi:10.3400/avd.oa.19-00007

Cited by 20 publications

(22 citation statements)

References 22 publications

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“…Previous studies show that neutrophil infiltration is predominant in the acute phase of human TAD [5][6][7] . In a murine model of thoracic aortic dissection, neutrophils were shown to be an important mediator in the initiation of TAD, as the antibody-mediated depletion of neutrophils attenuated TAD formation 7 .…”

Section: Discussionmentioning

confidence: 99%

“…However, the direct cellular and molecular mechanism that is involved in the onset of TAD has not been fully elucidated. Several studies reported that neutrophil infiltration is predominant in the acute phase of human TAD [5][6][7] . CD44 is a widely distributed cell surface marker and cell adhesion molecule that serves as a principle receptor for extracellular matrix components such as hyaluronan 8,9 , Under inflammatory conditions, CD44 is upregulated on inflammatory cells including neutrophils, monocytes, and lymphocytes 10 .…”

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confidence: 99%

“…Various Neutrophil migration to TAD lesions requires CD44. Several studies reported that neutrophil infiltration was predominant in the acute phase of human TAD [5][6][7] . Therefore, to examine the thoracic adventitial infiltration of vascular inflammatory cells during the acute stage in the TAD model, immunofluorescence staining for LY6 (neutrophils) and CD68 (macrophages) was performed 1 day after BAPN/AngII infusion.…”

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confidence: 99%

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Deficiency of CD44 prevents thoracic aortic dissection in a murine model

Hatipoğlu

Miyoshi

Yonezawa

et al. 2020

Sci Rep

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Thoracic aortic dissection (TAD) is a life-threatening vascular disease. We showed that CD44, a widely distributed cell surface adhesion molecule, has an important role in inflammation. In this study, we examined the role of CD44 in the development of TAD. TAD was induced by the continuous infusion of β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, and angiotensin II (AngII) for 7 days in wild type (WT) mice and CD44 deficient (CD44 -/-) mice. The incidence of TAD in CD44 -/mice was significantly reduced compared with WT mice (44% and 6%, p < 0.01). Next, to evaluate the initial changes, aortic tissues at 24 hours after BAPN/AngII infusion were examined. Neutrophil accumulation into thoracic aortic adventitia in CD44 -/mice was significantly decreased compared with that in WT mice (5.7 ± 0.3% and 1.6 ± 0.4%, p < 0.01). In addition, BAPN/AngII induced interleukin-6, interleukin-1β, matrix metalloproteinase-2 and matrix metalloproteinase-9 in WT mice, all of which were significantly reduced in CD44 −/− mice (all p < 0.01). In vitro transmigration of neutrophils from CD44 −/− mice through an endothelial monolayer was significantly decreased by 18% compared with WT mice (p < 0.01). Our findings indicate that CD44 has a critical role in TAD development in association with neutrophil infiltration into adventitia. open Scientific RepoRtS | (2020) 10:6869 | https://doi.org/10.1038/s41598-020-63824-9www.nature.com/scientificreports www.nature.com/scientificreports/ routes of administration including oral gavage 7,14 , subcutaneous osmotic pump infusion 15 , and subcutaneous injection 16,17 , have previously been established. In the current study, we investigated the role of CD44 in TAD induced by BAPN/AngII by comparing wild type (WT) and CD44 deficient (CD44 −/− ) mice. Results CD44 deficiency in mice decreases rates of aortic dissection.To investigate the effects of CD44 deficiency on the development of aortic dissection, WT and CD44 −/− mice were administered saline or BAPN/AngII for 7 days (Fig. 1). Saline-treated WT and CD44 −/− mice were used as controls. A slight increase in blood pressure after treatment with BAPN/AngII was observed in WT and CD44 −/− mice (Supplemental Fig. 1). Treatment with BAPN/AngII led to thoracic and abdominal aortic dissection (the presence of an intramural thrombus) and rupture. Figure 2A shows a representative image of TAD (white arrow). Histological analyses in thoracic aortae showed that intramural haematoma (black arrow) and degradation of elastin (yellow arrow) were present in the dissection area (Fig. 2B). The incidence of aortic dissection in BAPN/AngII-treated CD44 −/− mice was approximately 0.4 times as high as the incidence in BAPN/AngII-treated WT mice (69% and 26%, p = 0.01) (Fig. 2C). Furthermore, the incidence of TAD after BAPN/AngII treatment was significantly reduced in CD44 −/− mice compared with WT mice (44% and 6%, p < 0.01). However, no difference in the incidence of abdominal aortic dissection was observed (25% and 20%, p = 0.76) ( Fig. 2D). Scientific RepoRtS...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Deficiency of CD44 prevents thoracic aortic dissection in a murine model

Hatipoğlu

Miyoshi

Yonezawa

et al. 2020

Sci Rep

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“…In an animal model, inflammation of the adventitia characterized by neutrophil recruitment was shown to promote tissue damage, leading to aortic dilation and rupture [8]. Moreover, a recent study of surgically resected aortic specimens revealed association between activation of STAT 3 in adventitial tissue and neutrophil infiltration [9].…”

Section: Introductionmentioning

confidence: 99%

Factors related to white blood cell elevation in acute type A aortic dissection

et al. 2020

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Aortic dissection may induce a systemic inflammatory reaction. The etiological backgrounds for elevation of the white blood cell count remain to be clarified. In 466 patients with acute type A aortic dissection treated surgically within 48 hours of symptom onset, the etiologic background of an elevated admission white blood cell count and the effect of such elevation on outcomes were assessed retrospectively. Patients' white blood cell count differed significantly in relation to the extent of dissection, with a median (25th, 75th percentile) white blood cell count of 10.4 (8.1, 13.9) x 10 3 /μL for dissection confined to the ascending aorta, 10.5 (8.2,13.) 10 3 /μL for dissection extending to the aortic arch/descending aorta, 11.1 (8.2, 13.7) x 10 3 /μL for extension to the abdominal aorta, and 13.3 (9.8, 15.9) x 10 3 /μL for extension to the iliac artery (p<0.001). With 11.0 x 10 3/ μL used as the cutoff value for white blood cell count elevation, multivariable analysis showed current smoking (p<0.001; odds ratio, 2.79), dissection extending to the iliac artery (p = 0.006; odds ratio, 1.79), age (p = 0.007, odds ratio, 0.98), and no coronary ischemia (p = 0.027, odds ratio, 2.22) to be factors related to the elevated white blood cell count. Mean age differed significantly between patients with and without an elevated white blood cell count (62.3 vs. 68.3 years, p <0.001). Although inhospital mortality was similar (7.5% vs.10.9%, p = 0.19), 5-year survival was lower in patients without an elevated count (85.7% vs. 78.6%, p = 0.019), reflecting their more advanced age. In conclusion, our data suggest that dissection morphology and patient age influence the acute phase systemic inflammatory response associated with an elevated white blood cell count in patients with ATAAD. A better understanding of this relation may help optimize diagnosis and perioperative care.

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“…Studies in human AD samples and animal AD models indicate that inflammatory response plays a central role in the pathogenesis of AD [3,4]. We also reported the involvement of inflammatory response in mouse models [5][6][7] and in human AD tissue [8]. Although these studies demonstrated the importance of inflammation, it remains elusive how inflammatory response is initiated or whether and how it is related to SMC cytoskeleton.…”

Section: Introductionmentioning

confidence: 79%

MRTF-A promotes angiotensin II-induced inflammatory response and aortic dissection in mice

et al. 2020

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Aortic dissection (AD) is a major cause of acute aortic syndrome with high mortality due to the destruction of aortic walls. Although recent studies indicate the critical role of inflammation in the disease mechanism of AD, it is unclear how inflammatory response is initiated. Here, we demonstrate that myocardin-related transcription factor A (MRTF-A), a signal transducer of humoral and mechanical stress, plays an important role in pathogenesis of AD in a mouse model. A mouse model of AD was created by continuous infusion of angiotensin II (AngII) that induced MRTF-A expression and caused AD in 4 days. Systemic deletion of Mrtfa gene resulted in a marked suppression of AD development. Transcriptome and gene annotation enrichment analyses revealed that AngII infusion for 1 day caused pro-inflammatory and pro-apoptotic responses before AD development, which were suppressed by Mrtfa deletion. AngII infusion for 1 day induced pro-inflammatory response, as demonstrated by expressions of Il6, Tnf, and Ccl2, and apoptosis of aortic wall cells, as detected by TUNEL staining, in an MRTF-A-dependent manner. Pharmacological inhibition of MRTF-A by CCG-203971 during AngII infusion partially suppressed AD phenotype, indicating that acute suppression of MRTF-A is effective in preventing the aortic wall destruction. These results indicate that MRTF-A transduces the stress of AngII challenge to the pro-inflammatory and proapoptotic responses, ultimately leading to AD development. Intervening this pathway may represent a potential therapeutic strategy.

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STAT3 Activation Correlates with Adventitial Neutrophil Infiltration in Human Aortic Dissection

Cited by 20 publications

References 22 publications

Deficiency of CD44 prevents thoracic aortic dissection in a murine model

Deficiency of CD44 prevents thoracic aortic dissection in a murine model

Factors related to white blood cell elevation in acute type A aortic dissection

MRTF-A promotes angiotensin II-induced inflammatory response and aortic dissection in mice

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