Expressions of Transforming Growth Factor β1 Signaling Cytokines in Aortic Dissection

Yuan, Shi‐Min; Lin, Hong

doi:10.21470/1678-9741-2018-0129

Cited by 11 publications

(10 citation statements)

References 34 publications

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“… 37 , 38 In addition, the SMAD signaling pathway can be activated in the extracellular matrix mediated by TGF‐β. 39 The TGF‐β1/SMAD signaling pathway was found to be significantly activated in patients with AD, 28 , 29 consistent with findings of this study. Furthermore, TGF‐β1 highly enhances the secretion of MMP9.…”

Section: Discussionsupporting

confidence: 83%

“…A previous study reported that the TGF‐β‐signaling pathway was activated in patients with AD. 28 , 29 Western blot analysis of the aorta samples showed that the level of TGF‐β1 was higher in the Col5a1 +/− group than in the WT group (Figure 3A and 3B ). Meanwhile, phosphorylation SMAD family member 2, total SMAD2, and the ratio of phosphorylation SMAD family member 2/SMAD2 increased significantly in the Col5a1 +/− group.…”

Section: Resultsmentioning

confidence: 96%

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COL5A1 Variants Cause Aortic Dissection by Activating TGF‐β‐Signaling Pathway

Chen

et al. 2021

JAHA

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Background Aortic dissection (AD) is one of the most life‐threatening cardiovascular diseases that exhibit high genetic heterogeneity. However, it is unclear whether variants within the COL5A1 gene can cause AD. Therefore, we intend to determine whether COL5A1 is a causative gene of AD. Methods and Results We performed targeted sequencing in 702 patients with unrelated sporadic AD and 163 matched healthy controls using a predesigned panel with 152 vessel matrix‐related genes. As a result, we identified that 11 variants in COL5A1 caused AD in 11 out of the 702 patients with AD. Furthermore, Col5a1 knockout ( Col5a1 +/− ) rats were generated through the CRISPR/Cas9 system. Although there was no spontaneous AD, electron microscopy revealed a fracture of elastic fibers and disarray of collagenous fibers in 6‐week‐old Col5a1 +/− rats, but not in WT rats (93.3% versus 0.0%, P <0.001). Three‐week‐old rats were used to induce the AD phenotype with β‐aminopropionitrile monofumarate for 4 weeks followed by angiotensin II for 72 hours. The β‐aminopropionitrile monofumarate and angiotensin II‐treated rat model confirmed that Col5a1 +/− rats had considerably higher AD incidence than WT rats. Subsequent mechanism analyses demonstrated that the transforming growth factor‐β‐signaling pathway was significantly activated in Col5a1 +/− rats. Conclusions Our findings, for the first time, revealed a relationship between variants in COL5A1 and AD via targeted sequencing in 1.57% patients with sporadic aortic dissection. The Col5a1 knockout rats exhibited AD after an intervention, indicating that COL5A1 is a causative gene of AD. Activation of the transforming growth factor‐β‐signaling pathway may be implicated in the pathogenesis of this kind of AD.

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Section: Discussionsupporting

confidence: 83%

Section: Resultsmentioning

confidence: 96%

COL5A1 Variants Cause Aortic Dissection by Activating TGF‐β‐Signaling Pathway

Chen

et al. 2021

JAHA

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“…38 Smads family represents the key intracellular effectors of TGF-b1, and the ligand of TGF-b1 could bind to Type II/Type I receptor to facilitate the phosphorylation of Smad2/3 which further binds to Smad4; and at the meantime, the resulting complex is translocated into the nucleus to up-regulate the expression of extracellular matrix, including a-SMA, collagen I and collagen III, eventually causing the tissue fibrosis or remodeling. [39][40][41] Furthermore, TGF-b stimulation induces myofibroblast differentiation and enhances extracellular matrixprotein synthesis by inhibiting MMP expression and inducing synthesis of protease inhibitors, such as TIMP. 42,43 Consistently, He et al found the TGF-b/Smad pathway inhibited by HMGB1 could suppress the expression of Col-I, Col-III and TIMP-2, thereby limiting the ventricular remodeling and improving the myocardial fibrosis.…”

Section: Discussionmentioning

confidence: 99%

N-myc downstream regulated gene 2 ameliorates myocardial remodeling and cardiac function in heart failure rats

Zhao

Mao

2021

Hum Exp Toxicol

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This study aims to explore the effect of NDRG2 (N-myc downstream regulated gene 2)-mediated Transforming growth factor-beta 1 (TGF-β1)/ Sma- and Mad-related protein (Smad) pathway in heart failure (HF) rats. HF rat models were established and treated with AdEGFP (adenovirus encoding enhanced green fluorescent protein) or AdNDRG2 (adenovirus encoding NDRG2). The echocardiography and hemodynamic parameters were detected, and the infarct size was calculated via 2,3,5-triphenyltetrazolium chloride (TTC) staining. Masson staining was performed to observe the collagen volume fraction (CVF), quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) to detect the expression of Collagen I (Col-I) and Collagen III (Col-III), and Transferase (TdT)-mediated D-UTP-biotin nick end labeling (TUNEL) staining to evaluate the apoptosis. Rats in the Model group presented with the decreases in left ventricular ejection fraction (LVEF), left ventricular shortening fraction (LVFS), left ventricular systolic pressure (LVSP) and maximal/minimum rate of left ventricular pressure (±dp/dt max), and significant increases in left ventricular end-diastolic pressure (LVEDP) and CVF. At the meantime, the expression of Col-I and Col-III as well as the apoptotic rate of myocardial cells was also elevated with increased infarct size in the Model group. The Model rats also had the significant reduction in the expression of NDRG2 and up-regulations of TGF-β1, p-Smad2/Smad2, p-Smad3/Smad3 and tissue inhibitor of metalloproteinases-2 (TIMP-2). However, model rats treated with AdNDRG2 had evident amelioration in aforementioned indicators. In conclusion, NDRG2 reduces the apoptosis of myocardial cells and improves the heart function and myocardial remodeling in HF rats via inhibiting the activity of TGF-β1/Smad.

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“…Eosinophils also express transforming growth factor-β, which is elevated in AD [36] and associated with an upregulation of matrix metalloproteinases [37][38]. Both are implicated in the vascular remodeling via collagen and extracellular matrix degradation [29,39]. Eosinophils release chemokines like CXC-motif chemokine ligand 8/IL-8, which can recruit leukocytes to the site of in ammation [40].…”

Section: Discussionmentioning

confidence: 99%

Impacts of eosinophil percentage on prognosis acute type A aortic dissection patients

Shao

Liu

Shi

et al. 2021

Preprint

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Background Eosinophils are pro-inflammatory cells involved in thrombosis and have been proposed as a prognosis marker in acute ischemic stroke and ST-elevation myocardial Infarction. Here, we sought to clarify the prognostic value of eosinophil percentage (EOS%) in patients with acute type A aortic dissection (AAAD). Methods We examined 183 consecutive AAAD patients. Based on the optimum cut-off value of EOS% determined by X-tile software, patients were classified into the low EOS% (EOS%≤0.1) and high EOS% groups (EOS%>0.1). We performed multivariate regression analysis and Kaplan-Meier (KM) survival curves to assess the association between EOS% and mortality. Eosinophil accumulation in aortic dissection intraluminal thrombus was confirmed using hematoxylin–eosin (H&E) staining. An external cohort from Medical Information Mart for Intensive Care IV was performed to validate the results. Results Relative to surviving patients, those who died during hospitalization had significantly lower EOS% (p=0.001) but significantly higher WBC (p=0.002) and neutrophil (p=0.001) counts. Multivariate regression analysis identified EOS% as an independent predictor of in-hospital and 1-year mortality. KM curves revealed that 1-year cumulative mortality was significantly higher in the low EOS% group, although it was mainly attributed to the higher 30-day mortality. H&E staining revealed massive infiltration of eosinophils in all 20 thrombus specimens. The external validation confirmed that relative to survivors, patients with in-hospital (p=0.010) had significantly lower EOS%. Moreover, multivariate regression analyses identified that decreased EOS% was independently significantly associated with in-hospital mortality. Conclusions Low EOS% is significantly related to increased mortality rates in AAAD patients.

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Expressions of Transforming Growth Factor β1 Signaling Cytokines in Aortic Dissection

Cited by 11 publications

References 34 publications

COL5A1 Variants Cause Aortic Dissection by Activating TGF‐β‐Signaling Pathway

COL5A1 Variants Cause Aortic Dissection by Activating TGF‐β‐Signaling Pathway

N-myc downstream regulated gene 2 ameliorates myocardial remodeling and cardiac function in heart failure rats

Impacts of eosinophil percentage on prognosis acute type A aortic dissection patients

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