Aortic Diameter Is Not an Accurate Predictor of Risk For Life-Threatening Rupture

Abdominal aortic aneurysm (AAAs) is a life threatening disease and currently the only treatment is surgical or endovascular repair. Using an animal model for AngiotensinII (AngII) mediated AAA formation in the ApoE-/- mouse, we demonstrate that AAA formation is dependent on the activation of the JAK/STAT pathway. STAT3 activity was increased in the abdominal aortas of Ang II treated ApoE-/- mice. Treatment of ApoE-/- mice with AngII and the p-STAT3 inhibitor S3I-201 decreased the incidence of AAA formation and aortic diameter by greater than 50% compared to placebo. While AngII treatment increased activity of MMP2 and MMP9 in aortas of ApoE-/- mice, S3I-201 treatment inhibited p-STAT3 stimulation and decreased MMP2 and MMP9 activity to levels similar to those in control aortas. The increase in p-STAT3 levels and the secretion of MMP2 and MMP9 in AngII treated bone marrow derived macrophages (BDMs) from ApoE-/- mice was inhibited by pretreatment with S3I-201. Interestingly, AngII stimulated TLR4 expression in AAAs and in BDMs from ApoE-/- mice. Based on these findings we determined the role of TLR4 on AAA formation and p-STAT3 stimulation in ApoE-/-TLR4-/- mice. The incidence of AAA formation, increase in aortic diameter and MMP2 and MMP9 activity were markedly decreased in AngII treated ApoE-/-TLR4-/- mice compared to ApoE-/- controls. Importantly, AngII stimulation of p-STAT3 was also decreased in ApoE-/-TLR4-/- mice compared to control. Similar effects on AngII stimulated p-STAT3 and activity of MMP2 and MMP9 were demonstrated in BMDs from ApoE-/-TLR4-/- mice. Treatment of ApoE-/- mice with the TLR4 inhibitor Eritoran (Eisai, Inc) also decreased the incidence and severity of AAAs, MMPs secretion and p-STAT3 activity. Finally, we determined that S3I-201 decreased AngII stimulated TLR4 expression in AngII treated ApoE-/- mice and in BDM from ApoE-/- mice compared to placebo. These data supported the conclusion that AngII stimulation of AAAs is mediated via a TLR4 dependent activation of p-STAT3 and that both p-STAT3 and TLR4 might be potential therapeutic targets for the treatment of AAAs.

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Abstract 66: TLR2 Signaling Protects Against Angiotensin II--Mediated AAA Formation in ApoE -/- Mice

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a66 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

Yali Zhang ◽

Ho-Jin Park ◽

Jessamyn Bagley ◽

Elena Maganto-Garcia ◽

John Kyriakis ◽

...

Keyword(s):

Angiotensin Ii ◽

Aortic Arch ◽

Thoracic Aorta ◽

Abdominal Aorta ◽

Chemokine Receptors ◽

Inflammatory Cells ◽

Aortic Diameter ◽

Ang Ii ◽

Life Threatening ◽

Tlr2 Signaling

Abdominal aortic aneurysm (AAA) is a potentially life-threatening degenerative vascular disease that affects 6-9% of men over 65. Although Toll-like receptors (TLRs) mediate the innate immune response resulting in the recruitment of inflammatory cells to the site of a range of pathogen-associated molecular patterns, they have also been implicated in immune tolerance. To determine the role of TLR2 signaling in AAA formation we compared AAA formation in ApoE -/- and ApoE-/-TLR2 -/- DKO mice using a mouse model for angiotensin II (ANGII) mediated AAA formation. Treatment of ApoE -/- mice with Alzet pumps releasing 750 ng/kg/min ANG II resulted in formation of AAAs in 75% of mice (n=23) and a mean increase in aortic diameter from 1.0 mm in saline treated controls to 2.15±0.15 mm, p<0.001 with no effect on the thoracic aorta and the aortic arch. Although the incidence of AAAs in ApoE-/-TLR2 -/- DKO mice compared to ApoE -/- alone was unchanged, of the 12 ApoE-/-TLR2-/-DKO who developed AAAs, half demonstrated severe aneurismal involvement of the aortic arch and thoracic aorta compared to the ApoE -/- group consistent with a protective effect of TLR2. To test this hypothesis, mice were pretreated with PAM3, 50ug/ mouse/week. The incidence of AAA formation decreased to 32% in PAM 3 treated mice and aortic diameter decreased to 1.17±0.08 (n=18, p<0.001) compared to ANGII alone. PAM3 had no effect on blood pressure or lipid levels. Furthermore, treatment with PAM3 after a 7 day ANG II infusion decreased the incidence of AAA to 53%. ANG II stimulated expression of the cytokines RANTES and CXCl10 and the receptor CCR5 more than 8 fold as measured by ELISA and western blot respectively; PAM3 treatment of these ANG II infused mice decreased expression to control levels in association with decreased macrophage infiltration. Finally, while ANG II increased the ratio of M1/M2 macrophages in the abdominal aorta by 2 fold, PAM3 treatment reversed the effect of ANG II on M1/M2 in aortas of mice that did not develop AAAs. Thus TLR2 stimulation protected the abdominal aorta from ANG II mediated AAA at least in part by attenuating recruitment of macrophages and expression of chemokines and chemokine receptors.

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Aortic wall inflammation: a more accurate predictor of aneurysm expansion and aneurysm rupture risk than aortic diameter?

Journal of Thoracic Disease ◽

10.21037/jtd.2018.09.36 ◽

2018 ◽

Vol 10 (S33) ◽

pp. S3865-S3866 ◽

Cited By ~ 1

Author(s):

Kosmas I. Paraskevas

Keyword(s):

Aortic Wall ◽

Aneurysm Rupture ◽

Aortic Diameter ◽

Rupture Risk ◽

Accurate Predictor

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Descending aortic diameter of 5.5 cm or greater is not an accurate predictor of acute type B aortic dissection

Journal of Thoracic and Cardiovascular Surgery ◽

10.1016/j.jtcvs.2010.12.032 ◽

2011 ◽

Vol 142 (3) ◽

pp. e101-e107 ◽

Cited By ~ 43

Author(s):

Santi Trimarchi ◽

Frederik H.W. Jonker ◽

Stuart Hutchison ◽

Eric M. Isselbacher ◽

Linda A. Pape ◽

...

Keyword(s):

Aortic Dissection ◽

Aortic Diameter ◽

Acute Type ◽

Type B ◽

Type B Aortic Dissection ◽

Accurate Predictor

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Assembly of VP26 in herpes simplex virus-1 capsid implicated by 3-D structure of recombinant capsid

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100140579 ◽

1995 ◽

Vol 53 ◽

pp. 840-841

Author(s):

Z. Hong Zhou ◽

Jing He ◽

Joanita Jakana ◽

J. D. Tatman ◽

Frazer J. Rixon ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

3D Structure ◽

Structure Study ◽

Herpes Simplex Virus 1 ◽

Shell Proteins ◽

Life Threatening ◽

Infected Cells ◽

Simplex Virus ◽

Hsv 1

Herpes simplex virus-1 (HSV-1) is a ubiquitous virus which is implicated in diseases ranging from self-curing cold sores to life-threatening infections. The 2500 Å diameter herpes virion is composed of a glycoprotein spike containing, lipid envelope, enclosing a protein layer (the tegument) in which is embedded the capsid (which contains the dsDNA genome). The B-, and A- and C-capsids, representing different morphogenetic stages in HSV-1 infected cells, are composed of 7, and 5 structural proteins respectively. The three capsid types are organized in similar T=16 icosahedral shells with 12 pentons, 150 hexons, and 320 connecting triplexes. Our previous 3D structure study at 26 Å revealed domain features of all these structural components and suggested probable locations for the outer shell proteins, VP5, VP26, VP19c and VP23. VP5 makes up most of both pentons and hexons. VP26 appeared to bind to the VP5 subunit in hexon but not to that in penton.

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An Overview of Dementias

Perspectives on Swallowing and Swallowing Disorders (Dysphagia) ◽

10.1044/sasd21.3.75 ◽

2012 ◽

Vol 21 (3) ◽

pp. 75-84

Author(s):

Venkata Vijaya K. Dalai ◽

Jason E. Childress ◽

Paul E Schulz

Keyword(s):

Clinical Presentation ◽

Treatment Options ◽

Current Treatment ◽

Great Variability ◽

Health Concern ◽

Public Health Concern ◽

Life Threatening ◽

The Common ◽

Neurodegenerative Dementias ◽

Made In

Dementia is a major public health concern that afflicts an estimated 24.3 million people worldwide. Great strides are being made in order to better diagnose, prevent, and treat these disorders. Dementia is associated with multiple complications, some of which can be life-threatening, such as dysphagia. There is great variability between dementias in terms of when dysphagia and other swallowing disorders occur. In order to prepare the reader for the other articles in this publication discussing swallowing issues in depth, the authors of this article will provide a brief overview of the prevalence, risk factors, pathogenesis, clinical presentation, diagnosis, current treatment options, and implications for eating for the common forms of neurodegenerative dementias.

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