Abstract 667: The Role of Aortic Wall-Nuclear Factor- kappa B (NF-kB) Signaling in Formation of Dissecting Aortic Aneurysms

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Talha Ijaz ◽  
Hong Sun ◽  
Adrian Recinos ◽  
Ronald G Tilton ◽  
Allan R Brasier
Keyword(s):  
Flow Cytometry ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Aortic Wall ◽  
Aortic Rupture ◽  
Aortic Aneurysms ◽  
Tunel Staining ◽  
Abdominal Aortic ◽  
Significant Difference

Introduction: Abdominal aortic aneurysm is a devastating disease since it can lead to aortic rupture and instantaneous death. We previously demonstrated that IL-6 secreted from the aortic wall is necessary for the development of abdominal aortic aneurysm and dissection (AAD). Since IL-6 is a NF-kB/RelA dependant gene, we investigated the role of aortic wall- NF-kB/RelA signaling in the development of AAD. Methods and Results: To test the role of aortic wall-RelA, we utilized Cre-Lox technology to delete RelA from aortic cells. Tamoxifen-inducible, Col1a2-promoter driven Cre mice (Col1a2-Cre) were crossed with mT/mG Cre-reporter mice to determine which aortic cells undergo genetic recombination after Cre activation. Flow cytometry analysis of the aortic wall indicated that 88% of the genetically recombined cells were SMCs and 8% were fibroblasts. Next, RelA floxed (RelA f/f) mice, generated in our lab, were crossed with Col1a2-Cre mice. RelA f/f Cre+ and RelA f/f Cre- were stimulated with tamoxifen for 10 days to generate aortic-RelA deficient (Ao-RelA-/-) or wild-type (Ao-RelA+/+) transgenics. Flow cytometry, qRT-PCR, and immunohistochemistry analysis suggested a depletion of aortic-RelA greater than 60%. To test the role of Ao-RelA in AAD, Ao-RelA -/- (n= 20) and Ao-RelA +/+ (n=14) mice were infused with angiotensin II for 7 days. Surprisingly, 20% of Ao-RelA-/- mice died from development of AAD and aortic rupture while no deaths were observed in Ao-RelA+/+ group. In addition, 40% of Ao-RelA-/- mice developed AAD compared to 14% of Ao-RelA+/+ mice. There was no significant difference in TUNEL staining or ERTR7+ fibroblast population between the two groups. Conclusion: Our studies suggest that aortic wall-RelA may be necessary for protection from AAD.

scholarly journals Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs

2019 ◽  
Vol 116 (26) ◽  
pp. 13006-13015 ◽  
Author(s):  
Wang Wang ◽  
Mengcheng Shen ◽  
Conrad Fischer ◽  
Ratnadeep Basu ◽  
Saugata Hazra ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Aortic Rupture ◽  
Critical Role ◽  
Neutral Endopeptidase ◽  
Negative Regulator ◽  
Ang Ii ◽  
Direct Role ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) remains the second most frequent vascular disease with high mortality but has no approved medical therapy. We investigated the direct role of apelin (APLN) in AAA and identified a unique approach to enhance APLN action as a therapeutic intervention for this disease. Loss of APLN potentiated angiotensin II (Ang II)-induced AAA formation, aortic rupture, and reduced survival. Formation of AAA was driven by increased smooth muscle cell (SMC) apoptosis and oxidative stress inApln−/yaorta and in APLN-deficient cultured murine and human aortic SMCs. Ang II-induced myogenic response and hypertension were greater inApln−/ymice, however, an equivalent hypertension induced by phenylephrine, an α-adrenergic agonist, did not cause AAA or rupture inApln−/ymice. We further identified Ang converting enzyme 2 (ACE2), the major negative regulator of the renin-Ang system (RAS), as an important target of APLN action in the vasculature. Using a combination of genetic, pharmacological, and modeling approaches, we identified neutral endopeptidase (NEP) that is up-regulated in human AAA tissue as a major enzyme that metabolizes and inactivates APLN-17 peptide. We designed and synthesized a potent APLN-17 analog, APLN-NMeLeu9-A2, that is resistant to NEP cleavage. This stable APLN analog ameliorated Ang II-mediated adverse aortic remodeling and AAA formation in an established model of AAA, high-fat diet (HFD) inLdlr−/−mice. Our findings define a critical role of APLN in AAA formation through induction of ACE2 and protection of vascular SMCs, whereas stable APLN analogs provide an effective therapy for vascular diseases.

scholarly journals Cyclic nucleotide phosphodiesterase 1C contributes to abdominal aortic aneurysm

2021 ◽  
Vol 118 (31) ◽  
pp. e2107898118
Author(s):  
Chongyang Zhang ◽  
Hongmei Zhao ◽  
Yujun Cai ◽  
Jian Xiong ◽  
Amy Mohan ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Cyclic Nucleotide ◽  
Aortic Aneurysms ◽  
Cyclic Nucleotide Phosphodiesterase ◽  
Causative Role ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) is characterized by aorta dilation due to wall degeneration, which mostly occurs in elderly males. Vascular aging is implicated in degenerative vascular pathologies, including AAA. Cyclic nucleotide phosphodiesterases, by hydrolyzing cyclic nucleotides, play critical roles in regulating vascular structure remodeling and function. Cyclic nucleotide phosphodiesterase 1C (PDE1C) expression is induced in dedifferentiated and aging vascular smooth muscle cells (SMCs), while little is known about the role of PDE1C in aneurysm. We observed that PDE1C was not expressed in normal aorta but highly induced in SMC-like cells in human and murine AAA. In mouse AAA models induced by Angiotensin II or periaortic elastase, PDE1C deficiency significantly decreased AAA incidence, aortic dilation, and elastin degradation, which supported a causative role of PDE1C in AAA development in vivo. Pharmacological inhibition of PDE1C also significantly suppressed preestablished AAA. We showed that PDE1C depletion antagonized SMC senescence in vitro and/or in vivo, as assessed by multiple senescence biomarkers, including senescence-associated β-galactosidase activity, γ-H2AX foci number, and p21 protein level. Interestingly, the role of PDE1C in SMC senescence in vitro and in vivo was dependent on Sirtuin 1 (SIRT1). Mechanistic studies further showed that cAMP derived from PDE1C inhibition stimulated SIRT1 activation, likely through a direct interaction between cAMP and SIRT1, which leads to subsequent up-regulation of SIRT1 expression. Our findings provide evidence that PDE1C elevation links SMC senescence to AAA development in both experimental animal models and human AAA, suggesting therapeutical significance of PDE1C as a potential target against aortic aneurysms.

scholarly journals Antithrombotic therapy in abdominal aortic aneurysm: beneficial or detrimental?

Blood ◽  
2018 ◽  
Vol 132 (25) ◽  
pp. 2619-2628 ◽  
Author(s):  
Scott J. Cameron ◽  
Hannah M. Russell ◽  
A. Phillip Owens
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Aortic Rupture ◽  
Complex Structure ◽  
Treatment Strategies ◽  
Inflammatory Cells ◽  
Vascular Pathology ◽  
Coagulation Cascade ◽  
Abdominal Aortic

Abstract Abdominal aortic aneurysm (AAA) is a degenerative vascular pathology resulting in significant morbidity and mortality in older adults due to rupture and sudden death. Despite 150 000 new cases and nearly 15 000 deaths annually, the only approved treatment of AAA is surgical or endovascular intervention when the risk for aortic rupture is increased. The goal of the scientific community is to develop novel pharmaceutical treatment strategies to reduce the need for surgical intervention. Because most clinically relevant AAAs contain a complex structure of fibrin, inflammatory cells, platelets, and red blood cells in the aneurysmal sac known as an intraluminal thrombus (ILT), antithrombotic therapies have emerged as potential pharmaceutical agents for the treatment of AAA progression. However, the efficacy of these treatments has not been shown, and the effects of shrinking the ILT may be as detrimental as they are beneficial. This review discusses the prospect of anticoagulant and antiplatelet (termed collectively as antithrombotic) therapies in AAA. Herein, we discuss the role of the coagulation cascade and platelet activation in human and animal models of AAA, the composition of ILT in AAA, a possible role of the ILT in aneurysm stabilization, and the implications of antithrombotic drugs in AAA treatment.

A Novel Mechanism Underlying Inflammatory Smooth Muscle Phenotype in Abdominal Aortic Aneurysm

2021 ◽  
Author(s):  
Dunpeng Cai ◽  
Chenming Sun ◽  
Gui Zhang ◽  
Xingyi Que ◽  
Ken Fujise ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Aortic Rupture ◽  
Ang Ii ◽  
Adenosine Deaminases ◽  
Abdominal Aortic ◽  
The Stability ◽  
Phenotypic Transition

Rationale: Abdominal aortic aneurysm (AAA) is a permanent and localized dilatation of abdominal aorta with potentially fatal consequence of aortic rupture. No effective pharmacological approach has been identified to limit AAA progression and rupture. AAA is characterized by extensive aortic wall matrix degradation that contributes to arterial wall remodeling and eventual rupture, in which smooth muscle cell (SMC) phenotypic transition and matrix metalloproteinases (MMP), especially MMP2 and MMP9, play critical roles. Objective: Our previous study showed that adenosine deaminases acting on RNA 1 (ADAR1) regulates SMC phenotype, which prompted us to study if ADAR1 is involved in AAA development. Methods and Results: We used angiotensin II (Ang II) infusion ApoE-/- mouse model combined with ADAR1 global and SMC-specific knockout to study the role of ADAR1 in AAA formation/dissection. Aortic transplantation was conducted to determine the importance of vascular cell ADAR1 in AAA development/dissection. Primary cultured SMC were used to study how ADAR1 regulates the inflammatory SMC phenotype and MMP production/activity. Patient specimens were obtained to investigate the relevance of ADAR1 expression to human AAA disease. ADAR1 was induced in abdominal aortic SMC in both mouse and human AAA tissues. Heterozygous knockout of ADAR1 diminished the Ang II-induced AAA/dissection in ApoE-/- mice. Mouse aortic transplantation showed that ADAR1 in vascular cells was essential for AAA formation. SMC-specific ADAR1 knockout reduced experimental AAA formation/dissection. Mechanistically, ADAR1 interacted with HuR to increase the stability of MMP2 and MMP9 mRNA, leading to increased MMP levels and activities. Conclusions: ADAR1 is novel regulator of AAA development/dissection, and thus may represent a potentially new therapeutic target to hinder AAA growth and rupture.

scholarly journals Endovascular Aortic Repair (EVAR) Method in The Management of Abdominal Aortic Aneurysm

2020 ◽  
Vol 2 (1) ◽  
pp. 53-7
Author(s):  
Abed Nego Okthara Sebayang ◽  
Niko Azhari Hidayat
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Aortic Rupture ◽  
Aortic Aneurysms ◽  
Endovascular Aortic Repair ◽  
Global Burden ◽  
Aortic Repair ◽  
Abdominal Aortic ◽  
Aorta Abdominalis ◽  
Global Burden Disease

Aortic disease is a collection of diseases of the aorta, which includes aortic aneurysms; acute aortic infections consisting of aortic dissection, intramular hematoma, penetration of atherosclerotic ulcers (PAU) and traumatic injury to the aorta; pseudoaneurysm; aortic rupture; Marfan syndrome; and congenital abnormalities such as coarctation of the aorta. One of the aortic diseases that cause the death rate to increase according to the 2010 Global Burden Disease is aortic aneurysm. Abdominal aortic aneurysm (AAA) is a focal dilatation of the aortic segment. The diagnosis of AAA is done by history taking, physical examination and supporting examination. Management at AAA aims to prevent aortic wall rupture. An alternative procedure without open surgery is endovascular aortic repair (EVAR) using prostheses. It is expected that through the EVAR method, mortality and morbidity due to AAA can be reduced. Keywords: abdominal aortic aneursym, EVAR, prostheses     Penyakit aorta merupakan kumpulan penyakit pada aorta yang meliputi aneurisma aorta; sindrom aorta akut berupa diseksi aorta, hematoma intramular, penetrating atherosclerosis ulcer (PAU) dan cedera akibat trauma pada aorta; pseudoaneurysm; ruptur aorta; sindrom Marfan; serta penyakit kongenital seperti koarktasio aorta. Salah satu penyakit aorta yang menyebabkan angka kematian meningkat menurut Global Burden Disease 2010 adalah aneurisma aorta. Aneurisma aorta abdominalis (AAA) merupakan dilatasi fokal pada segmen aorta. Penegakan diagnosis AAA dilakukan dengan anamnesis, pemeriksaan fisik dan pemeriksaan penunjang. Penatalaksanaan pada AAA bertujuan untuk mencegah pecahnya dinding aorta. Prosedur alternatif tanpa pembedahan terbuka yang dijadikan pilihan adalah endovascular aortic repair (EVAR) menggunakan protesa. Diharapkan melalui metode EVAR angka mortalitas dan morbiditas akibat AAA dapat diturunkan. Kata kunci: aneurisma aorta abdominalis, EVAR, protesa

scholarly journals Inhibition of Peptidyl Arginine Deiminase 4-Dependent Neutrophil Extracellular Trap Formation Reduces Angiotensin II-Induced Abdominal Aortic Aneurysm Rupture in Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Ming Wei ◽  
Xia Wang ◽  
Yanting Song ◽  
Di Zhu ◽  
Dan Qi ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Tissue Injury ◽  
Arginine Deiminase ◽  
Tunel Staining ◽  
Ang Ii ◽  
Elastin Degradation ◽  
Abdominal Aortic

Objective: Neutrophil infiltration plays an important role in the initiation and development of abdominal aortic aneurysm (AAA). Recent studies suggested that neutrophils could release neutrophil extracellular traps (NETs), leading to tissue injury in cardiovascular diseases. However, the role of NETs in AAA is elusive. This study aimed to investigate the role and underlying mechanism of NETs in AAA development.Methods and Results: An angiotensin II (Ang II) infusion-induced AAA model was established to investigate the role of NETs during AAA development. Immunofluorescence staining showed that citrullinated histone 3 (citH3), myeloperoxidase (MPO), and neutrophil elastase (NE) (NET marker) expressions were significantly increased in Ang II-infused ApoE−/− mice. The circulating double-stranded DNA (dsDNA) level was also elevated, indicating the increased NET formation during AAA. PAD4 inhibitor YW3-56 inhibited Ang II-induced NET formation. Disruption of NET formation by YW3-56 markedly reduced Ang II-induced AAA rupture, as revealed by decreased aortic diameter, vascular smooth muscle cell (VSMC) apoptosis, and elastin degradation. Apoptosis of VSMC was evaluated by TUNEL staining and Annexin V-FITC/PI staining through flow cytometry. Western blot and inhibition experiments revealed that NETs induced VSMC apoptosis via p38/JNK pathway, indicating that PAD4-dependent NET formation played an important role in AAA.Conclusions: This study suggests that PAD4-dependent NET formation is critical for AAA rupture, which provides a novel potential therapeutic strategy for AAA disease.

Abstract 668: The Role of IL-27 Receptor Signaling in the Development of Abdominal Aortic Aneurysm

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Iuliia Peshkova ◽  
Petr Makhov ◽  
Vivianly Hou ◽  
Ekaterina Koltsova
Keyword(s):  
T Cells ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Inflammatory Cytokines ◽  
Aortic Wall ◽  
Lymphoid Cells ◽  
Dependent Manner ◽  
Enhanced Production ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) is a cardiovascular disease, which is characterized by aortic wall dilation with subsequent rupture and internal bleeding. Inflammatory reactions in the vessel wall are likely essential for AAA pathogenesis, just like they are important for the development of another vascular pathology- atherosclerosis, which can predispose to AAA formation in a context-dependent manner. While inflammatory cytokines were shown to promote atherosclerosis and AAA, little is known about contribution of anti-inflammatory cytokines with regard to their ability to control vascular inflammation. Interleukin (IL)-27 signaling is required to suppress atherosclerosis development but its function in AAA remains unknown. We utilize Angiotensin II (AngII) model to evaluate the role of IL-27R signaling in pathogenesis of AAA. AngII containing pumps were surgically implanted into Il27ra-/- x Ldlr-/-; Il27ra -/- x Apoe-/- and Il27ra+/- littermate controls and AAA progression was analyzed 4 weeks later. Surprisingly, we found attenuated AAA progression in Il27ra-/- mice compared to Il27ra+/- and wt counterparts. The latter developed large AAA with visual hemorrhage into the artery wall, while Il27ra-/- mice developed small AAA with fewer myeloid cells and T cells. Moreover, opposite to aortic arches, T cells in abdominal aortas of Il27ra-/- mice produced less inflammatory IL-17A, while IFNγ production was unchanged. Interestingly, we found enhanced production of “Th2-like” cytokines IL-4 and IL-13, by NK cells and Type 2 Innate lymphoid cells (ILC2) in Il27ra deficient mice, which correlated with the protection from AAA. Overall, we conclude that immunoregulatory cytokine IL-27 can differentially control atherosclerosis and AAA development by regulating innate and adaptive immune cell recruitment and cytokine production in the aortic wall.

Current evidence and prospects for medical treatment of abdominal aortic aneurysms

VASA ◽  
2005 ◽  
Vol 34 (4) ◽  
pp. 217-223 ◽  
Author(s):  
Diehm ◽  
Schmidli ◽  
Dai-Do ◽  
Baumgartner
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Medical Treatment ◽  
Endovascular Treatment ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Current Evidence ◽  
Significant Morbidity ◽  
Abdominal Aortic ◽  
Risk Of Rupture

Abdominal aortic aneurysm (AAA) is a potentially fatal condition with risk of rupture increasing as maximum AAA diameter increases. It is agreed upon that open surgical or endovascular treatment is indicated if maximum AAA diameter exceeds 5 to 5.5cm. Continuing aneurysmal degeneration of aortoiliac arteries accounts for significant morbidity, especially in patients undergoing endovascular AAA repair. Purpose of this review is to give an overview of the current evidence of medical treatment of AAA and describe prospects of potential pharmacological approaches towards prevention of aneurysmal degeneration of small AAAs and to highlight possible adjunctive medical treatment approaches after open surgical or endovascular AAA therapy.

Gender differences in abdominal aortic aneurysm therapy – a systematic review

VASA ◽  
2018 ◽  
Vol 47 (4) ◽  
pp. 267-272 ◽  
Author(s):  
Konstanze Stoberock ◽  
Tilo Kölbel ◽  
Gülsen Atlihan ◽  
Eike Sebastian Debus ◽  
Nikolaos Tsilimparis ◽  
...  
Keyword(s):  
Gender Differences ◽  
Abdominal Aortic Aneurysm ◽  
Survival Rate ◽  
Aortic Aneurysm ◽  
Endovascular Treatment ◽  
Aortic Aneurysms ◽  
Lower Survival Rate ◽  
Lower Survival ◽  
Abdominal Aortic ◽  
Risk Of Rupture

Abstract. This article analyses if and to what extent gender differences exist in abdominal aortic aneurysm (AAA) therapy. For this purpose Medline (PubMed) was searched from January 1999 to January 2018. Keywords were: “abdominal aortic aneurysm”, “gender”, “prevalence”, “EVAR”, and “open surgery of abdominal aortic aneurysm”. Regardless of open or endovascular treatment of abdominal aortic aneurysms, women have a higher rate of complications and longer hospitalizations compared to men. The majority of studies showed that women have a lower survival rate for surgical and endovascular treatment of abdominal aneurysms after both elective and emergency interventions. Women receive less surgical/interventional and protective medical treatment. Women seem to have a higher risk of rupture, a lower survival rate in AAA, and a higher rate of complications, regardless of endovascular or open treatment. The gender differences may be due to a higher age of women at diagnosis and therapy associated with higher comorbidity, but also because of genetic, hormonal, anatomical, biological, and socio-cultural differences. Strategies for treatment in female patients must be further defined to optimize outcome.

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