Increased Risk of Aortic Dissection with Perlecan Deficiency

Perlecan (HSPG2), a basement membrane-type heparan sulfate proteoglycan, has been implicated in the development of aortic tissue. However, its role in the development and maintenance of the aortic wall remains unknown. Perlecan-deficient mice (Hspg2−/−-Tg: Perl KO) have been found to show a high frequency (15–35%) of aortic dissection (AD). Herein, an analysis of the aortic wall of Perl KO mice revealed that perlecan deficiency caused thinner and partially torn elastic lamina. Compared to the control aortic tissue, perlecan-deficient aortic tissue showed a significant decrease in desmosine content and an increase in soluble tropoelastin levels, implying the presence of immature elastic fibers in Perl KO mice. Furthermore, the reduced expression of the smooth muscle cell contractile proteins actin and myosin in perlecan-deficient aortic tissue may explain the risk of AD. This study showed that a deficiency in perlecan, which is localized along the elastic lamina and at the interface between elastin and fibrillin-1, increased the risk of AD, largely due to the immaturity of extracellular matrix in the aortic tissue. Overall, we proposed a new model of AD that considers the deficiency of extracellular molecule perlecan as a risk factor.

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Decreased expression of fibulin-4 in aortic wall of aortic dissection

Vascular ◽

10.1177/1708538112473976 ◽

2013 ◽

Vol 22 (1) ◽

pp. 35-41 ◽

Cited By ~ 1

Author(s):

P Huawei ◽

C Qian ◽

T Chuan ◽

L Lei ◽

W Liang ◽

...

Keyword(s):

Polymerase Chain Reaction ◽

Aortic Dissection ◽

Aortic Wall ◽

Quantitative Polymerase Chain Reaction ◽

Artery Bypass ◽

Elastic Fiber ◽

Elastic Fibers ◽

Control Group ◽

Chain Reaction ◽

Polymerase Chain

In this research, we will examine the expression of Fibulin-4 in aortic wall to find out its role in aortic dissection development. The samples of aortic wall were obtained from 10 patients operated for acute ascending aortic dissection and five patients for chronic ascending aortic dissection. Another 15 pieces of samples from patients who had coronary artery bypass were as controls. The aortic samples were stained with aldehyde magenta dyeing to evaluate the arrangement of elastic fibers. The Fibulin-4 protein and mRNA expression were both determined by Western blot and realtime quantitative polymerase chain reaction. Compared with the control group, both in acute and chronic ascending aortic dissection, elastic fiber fragments increased and the expression of fibulin-4 protein significantly decreased ( P = 0.045 < 0.05). The level of fibulin-4 mRNA decreased in acute ascending aortic dissection ( P = 0.034 < 0.05), while it increased in chronic ascending aortic dissection ( P = 0.004 < 0.05). The increased amounts of elastic fiber fragments were negatively correlated with the expression of fibulin-4 mRNA in acute ascending aortic dissection. In conclusion, in aortic wall of ascending aortic dissection, the expression of fibulin-4 protein decreased and the expression of fibulin-4 mRNA was abnormal. Fibulin-4 may play an important role in the pathogenesis of aortic dissection.

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Angiotensin II Infusion Leads to Aortic Dissection in LRP8 Deficient Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21144916 ◽

2020 ◽

Vol 21 (14) ◽

pp. 4916

Author(s):

Jeremy Lagrange ◽

Stefanie Finger ◽

Sabine Kossmann ◽

Venkata Garlapati ◽

Wolfram Ruf ◽

...

Keyword(s):

Angiotensin Ii ◽

Aortic Dissection ◽

Immune Cells ◽

Vascular Reactivity ◽

Vascular Inflammation ◽

Low Density Lipoprotein ◽

Myeloid Cells ◽

Density Lipoprotein ◽

Aortic Tissue ◽

Deficient Mice

Myeloid cells are crucial for the development of vascular inflammation. Low-density lipoprotein receptor-related protein 8 (LRP8) or Apolipoprotein E receptor 2 (ApoER2), is expressed by macrophages, endothelial cells and platelets and has been implicated in the development of cardiovascular diseases. Our aim was to evaluate the role of LRP8, in particular from immune cells, in the development of vascular inflammation. Methods. LRP8+/+ and LRP8−/− mice (on B6;129S background) were infused with angiotensin II (AngII, 1 mg/kg/day for 7 to 28 day) using osmotic minipumps. Blood pressure was recorded using tail cuff measurements. Vascular reactivity was assessed in isolated aortic segments. Leukocyte activation and infiltration were assessed by flow cytometry of aortic tissue and intravital videomicroscopy imaging. Histological analysis of aortic sections was conducted using sirius red staining. Results. AngII infusion worsened endothelial-dependent vascular relaxation and immune cells rolling and adherence to the carotid artery in both LRP8+/+ as well as LRP8−/− mice. However, only LRP8−/− mice demonstrated a drastically increased mortality rate in response to AngII due to aortic dissection. Bone marrow transplantation revealed that chimeras with LRP8 deficient myeloid cells phenocopied LRP8−/− mice. Conclusion. AngII-infused LRP8 deficient mice could be a useful animal model to study aortic dissection reflecting the lethality of this disease in humans.

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Augmented effects of methionine and cholesterol in decreasing the elastic lamina while thickening the aortic wall in the rat aorta

Clinical Science ◽

10.1042/cs0950589 ◽

1998 ◽

Vol 95 (5) ◽

pp. 589-593 ◽

Cited By ~ 6

Author(s):

Anthony ZULLI ◽

Brian F. BUXTON ◽

Laurie DOOLAN ◽

James J. LIU

Keyword(s):

Aortic Wall ◽

Rat Aorta ◽

Chow Group ◽

Elevated Plasma ◽

Cholesterol Feeding ◽

Two Agents ◽

Increased Risk ◽

Normal Chow ◽

Aortic Wall Thickness ◽

Elastic Lamina

1.Patients with an elevated plasma level of either homocysteine or cholesterol are at increased risk of cardiovascular disease. Both methionine, the precursor of homocysteine, and cholesterol are found primarily in the same foods; therefore we investigated the effect of methionine feeding alone, cholesterol feeding alone, and both, on the thickness of the aortic wall and the aortic elastic lamina of normotensive animals. 2.Twenty normotensive rats were divided into four groups of five animals. The following diet was administered for 15 weeks: normal chow; normal chow supplemented with 2% methionine; normal chow supplemented with 2% cholesterol; normal chow supplemented with 2% methionine+2% cholesterol. 3.The results showed a 3-fold decrease (P< 0.003) in the aortic elastic lamina in the 2% methionine group and a 2.5-fold decrease in the 2% cholesterol group compared with the normal chow group. There was a 9-fold (P< 0.0003) decrease in the 2% methionine+2% cholesterol group compared with the normal chow group. Furthermore, feeding with methionine plus cholesterol significantly increased aortic wall thickness compared with the methionine group, cholesterol group or control. 4.These results demonstrate an augmented effect of cholesterol plus methionine in the deterioration of the aortic elastic lamina, and furthermore, the combination of these two agents increases the thickness of the aortic wall. The results indicate a more important role for these two agents in combination than for either agent alone.

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P6494Activation of focal adhesion kinase is involved in pathogenesis of aortic dissection in mice

European Heart Journal ◽

10.1093/eurheartj/ehz746.1084 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

R Majima ◽

H Aoki ◽

Y Hashimoto ◽

M Hayashi ◽

S Ohno-Urabe ◽

...

Keyword(s):

Aortic Dissection ◽

Western Blot ◽

Focal Adhesion ◽

Transcriptome Analysis ◽

Aortic Wall ◽

Treated Group ◽

Immunofluorescence Staining ◽

Actin Dynamics ◽

Aortic Tissue ◽

Immunochemical Staining

Abstract Background Aortic dissection (AD) is a fatal disease where the media of the aorta suddenly fail. Currently, Molecular pathogenesis of AD is unknown. Recently, we discovered that the activity of MRTF-A, a mechanosensitive transcriptional regulator, promotes AD development. The activity of MRTF-A is regulated by mechanical stress to cells, which is transduced through focal adhesion and actin dynamics. However, it is currently unknown whether the mechanotransduction mechanism is involved in AD pathogenesis. Purpose We investigated the role of focal adhesion kinase (FAK), a signaling molecule that transduces mechanostress from focal adhesion to actin dynamics, in AD pathogenesis. Methods 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 + AngII) by an osmotic pump. This model caused about 60% death in all mice due to AD rupture within 2 weeks. In this model, we examined the severity and mortality rate of aortic dissection after 2 weeks in mice administered with PND-1186, an orally available FAK inhibitor, and in those treated with vehicle (n=20 for each group). We performed immunochemical staining, immunofluorescence staining and Western blot for activated (phosphorylated) FAK (pFAK) to evaluate the activation status of FAK in the aortic tissue. We also performed transcriptome analysis of the aortic tissue in with and without PND-1186 with BAPN + AngII stimulation before AD development. Results Immunochemical staining revealed that FAK was inactive in normal mouse aorta, but was strongly activated in the aortic walls after AD development. Immunofluorescence staining showed that FAK was activated mainly in smooth muscle cells after AD development. Western blot analysis also revealed that FAK was activated in 3 days after BAPN + AngII infusion before AD development, followed by transient reduction at day 7, and re-activation after AD at day 14. Significantly, administration of PND-1186 resulted in a significant reduction in the severity of AD in the aortic arch (1.96±0.41 mm in vehicle group, 0.66±0.29 mm in PND group, P<0.05). In addition, survival rate improved from 36.4% to 80.0% by administration of PND-1186 (P<0.01). In immunofluorescence staining, the PND-1186 treated group showed weaker staining of pFAK. Transcriptome analysis showed that genes for hematopoiesis and immune system were suppressed in PND-1186 treated group. Conclusions These findings proved that FAK plays a central role in the pathogenesis of AD probably by transmitting pathological stress to the aortic wall to cause tissue destruction. We propose that FAK is a potential therapeutic target for limiting the fatal destruction of the aortic wall of AD.

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Elastic Fibers of the Internal Elastic Lamina Are Unraveled But Not Created With Expanding Arterial Diameter in Arteriogenesis

JVS: Vascular Science ◽

10.1016/j.jvssci.2020.11.002 ◽

2020 ◽

Vol 1 ◽

pp. 247

Author(s):

Derek Afflu ◽

Dylan D. McCreary ◽

Nolan Skirtich ◽

Kathy Gonzalez ◽

Edith Tzeng ◽

...

Keyword(s):

Elastic Fibers ◽

Internal Elastic Lamina ◽

Arterial Diameter ◽

Elastic Lamina

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Aggrecan: a new biomarker for acute type A aortic dissection

Scientific Reports ◽

10.1038/s41598-021-89653-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Karl C. König ◽

Harald Lahm ◽

Martina Dreßen ◽

Stefanie A. Doppler ◽

Stefan Eichhorn ◽

...

Keyword(s):

Aortic Dissection ◽

Troponin T ◽

Type A ◽

Aortic Aneurysms ◽

Aortic Tissue ◽

Acute Type ◽

Type A Aortic Dissection ◽

Potential Biomarker ◽

Aortic Pathology ◽

Creatine Kinase Mb

AbstractAcute type A aortic dissection (ATAAD) constitutes a life-threatening aortic pathology with significant morbidity and mortality. Without surgical intervention the usual mortality rate averages between 1 and 2% per hour. Thus, an early diagnosis of ATAAD is of pivotal importance to direct the affected patients to the appropriate treatment. Preceding tests to find an appropriate biomarker showed among others an increased aggrecan (ACAN) mRNA expression in aortic tissue of ATAAD patients. As a consequence, we investigated whether ACAN is a potential biomarker for diagnosing ATAAD. Mean ACAN protein concentration showed a significantly higher plasma concentration in ATAAD patients (38.59 ng/mL, n = 33) compared to plasma of patients with thoracic aortic aneurysms (4.45 ng/mL, n = 13), patients with myocardial infarction (11.77 ng/mL, n = 18) and healthy volunteers (8.05 ng/mL, n = 12). Cardiac enzymes like creatine kinase MB and cardiac troponin T showed no correlation with ACAN levels in ATAAD patients. Receiver-operator characteristics (ROC) curve analysis for ATAAD patients versus control subjects an optimum discrimination limit of ACAN plasma levels at 14.3 ng/mL with a corresponding sensitivity of 97% and specificity of 81%. According to our findings ACAN is a reliable potential biomarker in plasma samples to detect ATAAD with high sensitivity and specificity.

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Mimicking the Mechanical Properties of Aortic Tissue with Pattern-Embedded 3D Printing for a Realistic Phantom

Materials ◽

10.3390/ma13215042 ◽

2020 ◽

Vol 13 (21) ◽

pp. 5042

Author(s):

Jaeyoung Kwon ◽

Junhyeok Ock ◽

Namkug Kim

Keyword(s):

Mechanical Properties ◽

Tensile Strength ◽

3D Printing ◽

Mechanical Characteristics ◽

Aortic Wall ◽

Tensile Tests ◽

Human Aorta ◽

Aortic Tissue ◽

Medical Field ◽

Base Materials

3D printing technology has been extensively applied in the medical field, but the ability to replicate tissues that experience significant loads and undergo substantial deformation, such as the aorta, remains elusive. Therefore, this study proposed a method to imitate the mechanical characteristics of the aortic wall by 3D printing embedded patterns and combining two materials with different physical properties. First, we determined the mechanical properties of the selected base materials (Agilus and Dragonskin 30) and pattern materials (VeroCyan and TPU 95A) and performed tensile testing. Three patterns were designed and embedded in printed Agilus–VeroCyan and Dragonskin 30–TPU 95A specimens. Tensile tests were then performed on the printed specimens, and the stress-strain curves were evaluated. The samples with one of the two tested orthotropic patterns exceeded the tensile strength and strain properties of a human aorta. Specifically, a tensile strength of 2.15 ± 0.15 MPa and strain at breaking of 3.18 ± 0.05 mm/mm were measured in the study; the human aorta is considered to have tensile strength and strain at breaking of 2.0–3.0 MPa and 2.0–2.3 mm/mm, respectively. These findings indicate the potential for developing more representative aortic phantoms based on the approach in this study.

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RAG-Mediated V(D)J Recombination Is Not Essential for Tumorigenesis in Atm-Deficient Mice

Molecular and Cellular Biology ◽

10.1128/mcb.22.9.3174-3177.2002 ◽

2002 ◽

Vol 22 (9) ◽

pp. 3174-3177 ◽

Cited By ~ 35

Author(s):

Lisa K. Petiniot ◽

Zoë Weaver ◽

Melanie Vacchio ◽

Rhuna Shen ◽

Danny Wangsa ◽

...

Keyword(s):

High Frequency ◽

Chromosomal Abnormalities ◽

Chromosomal Translocations ◽

Thymic Lymphoma ◽

Double Stranded Dna ◽

Break Repair ◽

Rag 1 ◽

Deficient Mice

ABSTRACT Atm-deficient mice die of malignant thymic lymphomas characterized by translocations within the Tcrα/δ locus, suggesting that tumorigenesis is secondary to aberrant responses to double-stranded DNA (dsDNA) breaks that occur during RAG-dependent V(D)J recombination. We recently demonstrated that development of thymic lymphoma in Atm−/− mice was not prevented by loss of RAG-2. Thymic lymphomas that developed in Rag2−/− Atm−/− mice contained multiple chromosomal abnormalities, but none of these involved the Tcrα/δ locus. These findings indicated that tumorigenesis in Atm−/− mice is mediated by chromosomal translocations secondary to aberrant responses to dsDNA breaks and that V(D)J recombination is an important, but not essential, event in susceptibility. In contrast to these findings, it was recently reported that Rag1−/− Atm−/− mice do not develop thymic lymphomas, a finding that was interpreted as demonstrating a requirement for RAG-dependent recombination in the susceptibility to tumors in Atm-deficient mice. To test the possibility that RAG-1 and RAG-2 differ in their roles in tumorigenesis, we studied Rag1−/− Atm−/− mice in parallel to our previous Rag2−/− Atm−/− study. We found that thymic lymphomas occur at high frequency in Rag1−/− Atm−/− mice and resemble those that occur in Rag2−/− Atm−/− mice. These results indicate that both RAG-1 and RAG-2 are necessary for tumorigenesis involving translocation in the Tcrα/δ locus but that Atm deficiency leads to tumors through a broader RAG-independent predisposition to translocation, related to a generalized defect in dsDNA break repair.

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Evaluation of neurodevelopment of preterm infants using Bayley III scale

Revista Brasileira de Saúde Materno Infantil ◽

10.1590/s1519-38292015000100004 ◽

2015 ◽

Vol 15 (1) ◽

pp. 47-55 ◽

Cited By ~ 5

Author(s):

Fernanda Veiga de Góes ◽

Maria Dalva B. B. Méio ◽

Rosane Reis de Mello ◽

Denise Morsch

Keyword(s):

Preterm Infants ◽

Motor Development ◽

High Frequency ◽

Expressive Language ◽

Cross Sectional Study ◽

Receptive Language ◽

Abnormal Development ◽

Cross Sectional ◽

Increased Risk ◽

Significant Difference

Objectives: to assess cognitive, motor, and language development in preterm infants, and perinatal, neonatal and socioeconomic factors associated with abnormal development. Methods: a cross-sectional study was carried out with 104 preterm infants (gestational ages < 33 weeks) (17 - 30 months corrected ages) using the Bayley III Scale. Logistic regression analysis was performed and prevalence ratios calculated. Results: the average language score (81.9) was low, while cognitive (93.7) and motor (91.1) scores were within normal values. There were deficiencies in receptive but not in expressive language. Male sex (OR 2.55 CI 1.01-6.44) and neonatal pneumonia (OR 33.85 CI 3.3-337.8) were associated with abnormal language scores. No factor was associated with abnormal cognitive scores; male gender indicated an increased risk of abnormal motor scores. The lack of a father was a risk factor for impaired motor development (PR: 2.96, CI: 5.6 - 1.55). There was no statistically significant difference in the development of small and appropriate for gestational age children. Conclusions: the Bayley III Scale was useful for assessing language and cognition separately, discriminating between receptive and expressive language. There was a high frequency of language deficiencies, especially in receptive language. Although motor and cognitive average scores were within the normal range, there was a high frequency of children with delayed development in these areas, especially motor development.

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