Role of c-Abl in Ang II-induced aortic dissection formation: Potential regulatory efficacy on phenotypic transformation and apoptosis of VSMCs

Life Sciences ◽  
2020 ◽  
Vol 256 ◽  
pp. 117882
Author(s):  
Xianwu Zhou ◽  
Jiancheng Cheng ◽  
Zerui Chen ◽  
Huadong Li ◽  
Shu Chen ◽  
...  
Keyword(s):  
Aortic Dissection ◽  
Ang Ii ◽  
Formation Potential ◽  
Phenotypic Transformation

Abstract 351: Focal Adhesion Kinase Promotes Tissue Destruction in Aortic Dissection in Mice

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Ryohei Majima ◽  
Hiroki Aoki ◽  
Eichi Nakao ◽  
Yohei Hashimoto ◽  
Sohei Ito ◽  
...  
Keyword(s):  
Aortic Dissection ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Suppressive Effect ◽  
Lesion Length ◽  
Ang Ii ◽  
Tissue Destruction ◽  
Potential Therapeutic Target ◽  
Mouse Aorta

Aortic dissection (AD) is a fatal disease due to the sudden destruction of the aortic medial layer. Currently, Molecular pathogenesis of AD is unknown. We investigated the role of focal adhesion kinase (FAK), a mechanosensitive signal transducer, in AD pathogenesis. We created a mouse model of AD with a continuous infusion of beta-aminopropionitrile (150 mg/kg/day), a collagen crosslink inhibitor, and angiotensin II (1,000 ng/kg/min) (BAPN + Ang II) by osmotic pumps. This AD model showed about 60% mortality within 2 weeks due to AD rupture. Immunohistochemical staining for activated FAK revealed that FAK was inactive in normal mouse aorta, but was strongly activated in the aortic walls after BAPN + Ang II infusion. Immunofluorescence staining showed that FAK was activated mainly in smooth muscle cells after the BAPN + Ang II challenge. Western blot analysis revealed that FAK was activated in 3 days after BAPN + Ang II infusion before AD development, followed by transient reduction at day 7, and re-activation after AD development at day 14. We examined the effect of PND-1186, an orally available FAK inhibitor, on the severity as determined by the AD lesion length and the mortality of AD. Mice were administered with either vehicle or PND-1186 (150 mg/kg twice daily by oral gavage) during the BAPN + Ang II challenge (n=20 for each group). Administration of PND-1186 resulted in significant reduction in the lesion length of AD (vehicle; 12.5 ± 1.65 mm, PND; 7.46 ± 1.88 mm, P<0.05). The suppressive effect of PND-1186 was most significant in the aortic arch (vehicle; 2.13 ± 0.29 mm, PND; 0.85 ± 0.22 mm, P<0.01). Furthermore, PND-1186 significantly improved the survival rate of mice from 40.0% to 80.0% (P<0.01). Transcriptome analysis indicated that destruction and inflammation of tissue were suppressed by PND-1186 administration. These findings indicated that FAK plays an important role in AD pathogenesis, possibly by transducing the pathological stress to the tissue destructive response in the aortic walls. We propose that FAK is a potential therapeutic target to limit the fatal destruction of aortic walls in AD.

scholarly journals Expression and role of lumican in acute aortic dissection: A human and mouse study

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0255238
Author(s):  
Shao-Wei Chen ◽  
Shing-Hsien Chou ◽  
Ying-Chang Tung ◽  
Fu-Chih Hsiao ◽  
Chien-Te Ho ◽  
...  
Keyword(s):  
Aortic Dissection ◽  
Aortic Rupture ◽  
Expression Patterns ◽  
Ang Ii ◽  
Mice Model ◽  
Tissue Integrity ◽  
Potential Biomarker ◽  
Life Threatening ◽  
Mouse Study

Introduction Aortic dissection (AD) is a life-threatening emergency, and lumican (LUM) is a potential Biomarker for AD diagnosis. We investigated LUM expression patterns in patients with AD and explored the molecular functions of Lum in AD mice model. Methods LUM expression patterns were analyzed using aortic tissues of AD patients, and serum soluble LUM (s-LUM) levels were compared between patients with acute AD (AAD) and chronic AD (CAD). Lum-knockout (Lum−/−) mice were challenged with β-aminopropionitrile (BAPN) and angiotensin II (Ang II) to induce AD. The survival rate, AD incidence, and aortic aneurysm (AA) in these mice were compared with those in BAPN–Ang II–challenged wildtype (WT) mice. Tgf-β/Smad2, Mmps, Lum, and Nox expression patterns were examined. Results LUM expression was detected in the intima and media of the ascending aorta in patients with AAD. Serum s-LUM levels were significantly higher in patients with AAD than CAD. Furthermore, AD-associated mortality and thoracic aortic rupture incidence were significantly higher in the Lum−/− AD mice than in the WT AD mice. However, no significant pathologic changes in AA were observed in the Lum−/− AD mice compared with the WT AD mice. The BAPN–Ang II–challenged WT and Lum−/− AD mice had higher Tgf-β, p-Smad2, Mmp2, Mmp9, and Nox4 levels than those of non-AD mice. We also found that Lum expression was significantly higher in the BAPN-Ang II–challenged WT in comparison to the unchallenged WT mice. Conclusion LUM expression was altered in patients with AD display increased s-LUM in blood, and Lum−/− mice exhibited augmented AD pathogenesis. These findings support the notion that LUM is a biomarker signifying the pathogenesis of injured aorta seen in AAD. The presence of LUM is essential for maintenance of connective tissue integrity. Future studies should elucidate the mechanisms underlying LUM association in aortic changes.

scholarly journals Altered DNA methylation pattern reveals epigenetic regulation of Hox genes in thoracic aortic dissection and serves as a biomarker in disease diagnosis

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Peiru Liu ◽  
Jing Zhang ◽  
Duo Du ◽  
Dandan Zhang ◽  
Zelin Jin ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Aortic Dissection ◽  
Epigenetic Regulation ◽  
Heart Development ◽  
Type A ◽  
Methylation Pattern ◽  
Healthy Controls ◽  
Global Methylation ◽  
Thoracic Aortic Dissection

Abstract Background Thoracic aortic dissection (TAD) is a severe disease with limited understandings in its pathogenesis. Altered DNA methylation has been revealed to be involved in many diseases etiology. Few studies have examined the role of DNA methylation in the development of TAD. This study explored alterations of the DNA methylation landscape in TAD and examined the potential role of cell-free DNA (cfDNA) methylation as a biomarker in TAD diagnosis. Results Ascending aortic tissues from TAD patients (Stanford type A; n = 6) and healthy controls (n = 6) were first examined via whole-genome bisulfite sequencing (WGBS). While no obvious global methylation shift was observed, numerous differentially methylated regions (DMRs) were identified, with associated genes enriched in the areas of vasculature and heart development. We further confirmed the methylation and expression changes in homeobox (Hox) clusters with 10 independent samples using bisulfite pyrosequencing and quantitative real-time PCR (qPCR). Among these, HOXA5, HOXB6 and HOXC6 were significantly down-regulated in TAD samples relative to controls. To evaluate cfDNA methylation pattern as a biomarker in TAD diagnosis, cfDNA from TAD patients (Stanford type A; n = 7) and healthy controls (n = 4) were examined by WGBS. A prediction model was built using DMRs identified previously from aortic tissues on methylation data from cfDNA. Both high sensitivity (86%) and specificity (75%) were achieved in patient classification (AUC = 0.96). Conclusions These findings showed an altered epigenetic regulation in TAD patients. This altered epigenetic regulation and subsequent altered expression of genes associated with vasculature and heart development, such as Hox family genes, may contribute to the loss of aortic integrity and TAD pathogenesis. Additionally, the cfDNA methylation in TAD was highly disease specific, which can be used as a non-invasive biomarker for disease prediction.

scholarly journals Role of Transesophageal Echocardiography in Patients With Suspected Aortic Dissection

2005 ◽  
Vol 18 (11) ◽  
pp. 1221.e5-1221.e7 ◽  
Author(s):  
H ELTZSCHIG ◽  
P ROSENBERGER ◽  
R LEKOWSKIJR ◽  
J SCOTT ◽  
A LOCKE ◽  
...  
Keyword(s):  
Aortic Dissection ◽  
Transesophageal Echocardiography

Effects of long-term chloroquine administration on the natural history of aortic aneurysms in mice

2015 ◽  
Vol 93 (8) ◽  
pp. 641-648 ◽  
Author(s):  
Azza Ramadan ◽  
Mark D. Wheatcroft ◽  
Adrian Quan ◽  
Krishna K. Singh ◽  
Fina Lovren ◽  
...  
Keyword(s):  
Natural History ◽  
Thrombus Formation ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Abdominal Aortic ◽  
Suprarenal Aorta ◽  
History Of ◽  
Categorical Distribution

Autophagy regulates cellular homeostasis and integrates the cellular pro-survival machinery. We investigated the role of autophagy in the natural history of murine abdominal aortic aneurysms (AAA). ApoE−/− mice were implanted with saline- or angiotensin II (Ang-II)-filled miniosmotic pumps then treated with either the autophagy inhibitor chloroquine (CQ; 50 mg·(kg body mass)–1·day–1, by intraperitoneal injection) or saline. Ang-II-elicited aneurysmal expansion of the suprarenal aorta coupled with thrombus formation were apparent 8 weeks later. CQ had no impact on the incidence (50% for Ang-II compared with 46.2% for Ang-II + CQ; P = NS) and categorical distribution of aneurysms. The markedly reduced survival rate observed with Ang-II (57.1% for Ang-II compared with 100% for saline; P < 0.05) was unaffected by CQ (61.5% for Ang-II + CQ; P = NS compared with Ang-II). CQ did not affect the mean maximum suprarenal aortic diameter (1.91 ± 0.19 mm for Ang-II compared with 1.97 ± 0.21 mm for Ang-II + CQ; P = NS). Elastin fragmentation, collagen accumulation, and smooth muscle attrition, which were higher in Ang-II-treated mice, were unaffected by CQ treatment. Long-term CQ administration does not affect the natural history and prognosis of experimental AAA, suggesting that global loss of autophagy is unlikely to be a causal factor in the development of aortic aneurysms. Manipulation of autophagy as a mechanism to reduce AAA may need re-evaluation.

The role of medical treatment of distal type aortic dissection

1991 ◽  
Vol 32 (2) ◽  
pp. 231-240 ◽  
Author(s):  
Kazuhiro Hara ◽  
Tetsu Yamaguchi ◽  
Yasuhiko Wanibuchi ◽  
Kiyoshi Kurokawa
Keyword(s):  
Aortic Dissection ◽  
Medical Treatment

Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression

2004 ◽  
Vol 287 (5) ◽  
pp. H1957-H1966 ◽  
Author(s):  
Faina Schwartz ◽  
Arvi Duka ◽  
Irena Duka ◽  
Jing Cui ◽  
Haralambos Gavras
Keyword(s):  
Gene Expression ◽  
Cardiac Remodeling ◽  
Unknown Function ◽  
Mouse Heart ◽  
Ang Ii ◽  
Coordinate Regulation ◽  
Transcriptional Changes ◽  
Novel Targets ◽  
Molecular Circuitry

Although the central role of ANG II in cardiovascular homeostasis is well appreciated, the molecular circuitry of its many actions is not completely understood. With the use of serial analysis of gene expression to assess global transcriptional changes in the heart of mice after continuous 7-day ANG II administration, we identified patterns of gene expression indicative of cardiac remodeling, including coordinate regulation of genes previously described in a context of processes associated with hypertrophy and fibrosis. In addition, we discovered several novel ANG II targets, including characterized genes of known function, recently annotated genes of unknown function, and the putative genes not yet present in current databases. The serial analysis of gene expression approach to assess the role of ANG II presented in this report provides new venues for inquiries into ANG II-mediated cardiac function.

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