One amino acid change of Angiotensin II diminishes its effects on abdominal aortic aneurysm

Abstract Angiotensin (Ang) A is formed by the decarboxylation of the N terminal residue of AngII. The present study determined whether this one amino acid change impacted effects of AngII on abdominal aortic aneurysm (AAA) formation in mice. Computational analyses implicated that AngA had comparable binding affinity to both AngII type 1 and 2 receptors as AngII. To compare effects of these two octapeptides in vivo, male low-density lipoprotein receptor (Ldlr) or apolipoprotein E (Apoe) deficient mice were infused with either AngII or AngA (1 μg/kg/min) for 4 weeks. While AngII infusion induced AAA consistently in both mouse strains, the equivalent infusion rate of AngA did not lead to AAA formation. We also determined whether co-infusion of AngA would influence AngII-induced aortic aneurysm formation in male Apoe−/− mice. Co-infusion of the same infusion rate of AngII and AngA did not change AngII-induced AAA formation. Since it was reported that a 10-fold higher concentration of AngA elicited comparable vasoconstrictive responses as AngII, we compared a 10-fold higher rate (10 μg/kg/min) of AngA infusion into male Apoe−/− mice with AngII (1 μg/kg/min). This rate of AngA led to abdominal aortic dilation in three of ten mice, but no aortic rupture, whereas the 10-fold lower rate of AngII infusion led to abdominal aortic dilation or rupture in eight of ten mice. In conclusion, AngA, despite only being one amino acid different from AngII, has diminished effects on aortic aneurysmal formation, implicating that the first amino acid of AngII has important pathophysiological functions.

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Real-time 3D catheter localization system using ultrasound: Recent in vivo results towards endovascular abdominal aortic aneurysm repair

2011 IEEE International Ultrasonics Symposium ◽

10.1109/ultsym.2011.0437 ◽

2011 ◽

Author(s):

Jay Mung ◽

Jesse Yen ◽

John Moos ◽

Fred Weaver

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Real Time ◽

Abdominal Aortic Aneurysm Repair ◽

Localization System ◽

Abdominal Aortic ◽

Catheter Localization ◽

Aneurysm Repair ◽

Aortic Aneurysm Repair

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Abstract 3718: MMP-12 Inhibitor Reduces Severity of ANGII-induced Aortic Abdominal Aneurysms in apoE−/− Mice

Circulation ◽

10.1161/circ.118.suppl_18.s_473-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Dawn A Savio ◽

Anita R Halpern ◽

Yuchuan Wu ◽

Wei Li ◽

Joseph Sypek ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Vascular Wall ◽

Inflammatory Disorder ◽

Gene Markers ◽

Genetic Ablation ◽

Macrophage Recruitment ◽

Aneurysm Formation ◽

Abdominal Aortic

Abdominal aortic aneurysm (AAA) is an inflammatory disorder characterized by local connective tissue degradation, macrophage recruitment and infiltration leading to aortic dilation and rupture. Aneurysms of the abdominal aorta represent a significant cardiovascular risk for which inflammation plays an integral role in the defined pathology. Genetic ablation of metalloprotease-12 (MMP-12) eliminates metalloelastase activity and attenuates aneurysm formation in apoE−/− mice. In the current study, a selective MMP-12 inhibitor, WAY-644 was evaluated in the well-established murine model of ANGII-induced aneurysm formation. This inhibitor displays activity for murine MMP-12, IC50 = 6.3 nM by FRET analysis, with low crossreactivity for other MMPs (exception MMP-8), and has established in vivo efficacy in inflammation models. Coadministration of WAY-644 to hyperlipidemic apoE−/− mice during ANGII infusion (1.44 mg/kg) for 28d alters the severity of AngII-induced AAAs as measured by changes in abdominal aortic wet weights and typical AAA classification. As expected, plasma MMP-12 protease activity measured by FRET analysis was inhibited. RNA profiling of abdominal aortic aneurysm tissue characterizes ANGII-induced AAA expansion driven by macrophage infiltration, destructive MMP production and attenuation by MMP-12 inhibition. The transcription of a subset of proinflammatory genes activated with ANGII treatment was repressed by the inhibitor. These genes include quantitative markers of macrophage accumulation in the vessel wall, CD68, MCP1/CCL2, CCR2, MMP-12, and Csf1. Associated reductions in gene markers for inflammation and oxidative stress, ie., heme oxidase (HO), nitric oxide synthase (nos2), Ikbkb, and Stat3 also correlate with MMP-12 antagonism. These changes occur in the absence of lipid changes (TC or TG), or quantitative changes in aortic arch lesions in the ANGII-infused animals. The findings support a mechanism whereby MMP-12 metalloelastase inactivation reduces macrophage recruitment to aneurysmal lesion sites, to lessen activated-macrophage expression of proinflammatory cytokines that figure prominently in vascular wall destruction and the pathogenesis of AAAs.

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Associations of IGF1 and its binding proteins with abdominal aortic aneurysm and aortic diameter in older men

Acta Endocrinologica ◽

10.1530/eje-11-0725 ◽

2012 ◽

Vol 166 (2) ◽

pp. 191-197 ◽

Cited By ~ 9

Author(s):

Bu B Yeap ◽

S A Paul Chubb ◽

Kieran A McCaul ◽

Leon Flicker ◽

Ken K Y Ho ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Binding Proteins ◽

Older Men ◽

Community Dwelling ◽

Aortic Diameter ◽

Aortic Dilation ◽

Cross Sectional ◽

Gh Secretion ◽

Abdominal Aortic

ObjectiveAbdominal aortic aneurysm (AAA) is most prevalent in older men. GH secretion declines with age resulting in reduced IGF1 levels. IGF1 and its binding proteins (IGFBPs) are expressed in vasculature, and lower IGF1 levels have been associated with cardiovascular risk factors and disease. However, the relationship of the IGF1 system with aortic dilation and AAA is unclear. We tested the hypothesis that circulating IGF1 and IGFBPs are associated with AAA and aortic diameter in older men.DesignA cross-sectional analysis involving 3981 community-dwelling men aged 70–89 years was performed.MethodsAbdominal aortic diameter was measured by ultrasound. Plasma total IGF1, IGFBP1 and IGFBP3 were measured by immunoassays.ResultsAfter adjustment for age, body mass index, waist:hip ratio, smoking, hypertension, dyslipidemia, diabetes, coronary heart disease and serum creatinine, a higher IGF1 level was associated with AAA (odds ratio (OR)/1 s.d. increase 1.18, 95% confidence interval (CI) 1.05–1.33, P=0.006), as was the ratio of IGF1/IGFBP3 (OR=1.22, 95% CI 1.10–1.35, P<0.001). Highest IGF1 concentrations compared with lowest quintile were significantly associated with AAA (quintile (Q) 5 vs Q1: OR=1.80, 95% CI 1.20–2.70, P=0.004) as were IGF1/IGFBP3 ratios (Q5 vs Q1: OR=2.52, 95% CI 1.59–4.02, P<0.001). IGF1 and IGFBP1 were independently associated with aortic diameter (β=0.200, 95% CI 0.043–0.357, P=0.012 and β=0.274, 95% CI 0.098–0.449, P=0.002 respectively).ConclusionsIn older men, higher IGF1 and an increased ratio of IGF1/IGFBP3 are associated with AAA, while IGFBP1 is independently associated with increased aortic diameter. Components of the IGF1 system may contribute to, or be a marker for, aortic dilation in ageing men.

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.667 ◽

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.

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Genetic and Epigenetic Mechanisms Underlying Vascular Smooth Muscle Cell Phenotypic Modulation in Abdominal Aortic Aneurysm

International Journal of Molecular Sciences ◽

10.3390/ijms21176334 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6334

Author(s):

Rijan Gurung ◽

Andrew Mark Choong ◽

Chin Cheng Woo ◽

Roger Foo ◽

Vitaly Sorokin

Keyword(s):

Smooth Muscle ◽

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Smooth Muscle Cells ◽

Aortic Wall ◽

Epigenetic Mechanisms ◽

Phenotypic Modulation ◽

Abdominal Aortic

Abdominal aortic aneurysm (AAA) refers to the localized dilatation of the infra-renal aorta, in which the diameter exceeds 3.0 cm. Loss of vascular smooth muscle cells, degradation of the extracellular matrix (ECM), vascular inflammation, and oxidative stress are hallmarks of AAA pathogenesis and contribute to the progressive thinning of the media and adventitia of the aortic wall. With increasing AAA diameter, and left untreated, aortic rupture ensues with high mortality. Collective evidence of recent genetic and epigenetic studies has shown that phenotypic modulation of smooth muscle cells (SMCs) towards dedifferentiation and proliferative state, which associate with the ECM remodeling of the vascular wall and accompanied with increased cell senescence and inflammation, is seen in in vitro and in vivo models of the disease. This review critically analyses existing publications on the genetic and epigenetic mechanisms implicated in the complex role of SMCs within the aortic wall in AAA formation and reflects the importance of SMCs plasticity in AAA formation. Although evidence from the wide variety of mouse models is convincing, how this knowledge is applied to human biology needs to be addressed urgently leveraging modern in vitro and in vivo experimental technology.

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Surface Parameterization of an Abdominal Aortic Aneurysm to Characterize Geometrical Evolution During Longitudinal Study of Patients

ASME 2012 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2012-80737 ◽

2012 ◽

Author(s):

A. Dupay ◽

P. Snyder ◽

W. Lee ◽

S. Baek

Keyword(s):

Abdominal Aortic Aneurysm ◽

Longitudinal Study ◽

Aortic Aneurysm ◽

Disease Progression ◽

3D Models ◽

Aortic Aneurysms ◽

Surrounding Tissue ◽

Geometrical Parameters ◽

Abdominal Aortic

For an abdominal aortic aneurysm (AAA) in vivo there are multiple tissues contacting its boundary, none of which have been fully considered for their effect throughout disease progression. Trends such as arterial asymmetry, surface curvature flattening, and arterial tortuosity could be significantly influenced by both surrounding tissue and hemodynamic factors. In order to quantify either the combined or separate influence of such factors during disease progression a precise characterization of aneurysm geometry evolution is needed. Multiple methods for geometrical parameterization of abdominal aortic aneurysms (AAAs) have been previously developed using isolated patient CT scan data but the focus has been mainly on the association of such geometrical parameters with the rupture risk and the efficacy of the parameterization is not fully investigated for a longitudinal study yet (multiple CT scans per patient at progressive intervals) [1]. For this study we have produced a series of 3D models for AAAs in longitudinal studies, developed an arterial centerline generation algorithm, and automated a geometric parameterization procedure for the arterial surfaces. It should be noted that the caliber of our collection of data is relatively rare as it is high resolution, features many patients, and on average has 4–5 images per patient.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1900152116 ◽

2019 ◽

Vol 116 (26) ◽

pp. 13006-13015 ◽

Cited By ~ 13

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.

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