Involvement of Vascular Angiotensin II-Forming Enzymes in the Progression of Aortic Abdominal Aneurysms in Angiotensin II- Infused ApoE-Deficient Mice

Inoue, Nao; Muramatsu, Michiko; Jin, Denan; Takai, Shinji; Hayashi, Toshio; Katayama, Hiroshi; Kitaura, Yasushi; Tamai, Hiroshi; Miyazaki, Mizuo

doi:10.5551/jat.e611

Cited by 33 publications

(31 citation statements)

References 36 publications

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“…While Wang and colleagues concede that another study failed to see worsening of aneurysms in TGFbNAb-treated Ang II-infused mice, they do not comment upon the fact that this study found that TGFbNAb afforded significant protection from Ang II-induced inflammatory aneurysms after Cxcl10 targeting - an event that accentuated aneurysm incidence and severity and death (23). It should also be noted that ARBs or silencing of expression of AT1R have been definitively shown to prevent Ang II-induced aneurysm in rodent models (24)(25)(26)(27)(28). If such manipulations attenuate TGF-b signaling in these models as in MFS (which remains to be demonstrated), then this would suggest that TGF-b antagonism is only nonproductive in the setting of (artificially?)…”

Section: Tgf-β and Models Of Abdominal Aortic Aneurysmmentioning

confidence: 99%

TGF-β in the pathogenesis and prevention of disease: a matter of aneurysmic proportions

Dietz¹

2010

J. Clin. Invest.

108

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Section: Tgf-β and Models Of Abdominal Aortic Aneurysmmentioning

confidence: 99%

TGF-β in the pathogenesis and prevention of disease: a matter of aneurysmic proportions

Dietz¹

2010

J. Clin. Invest.

108

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“…35 In contrast, several previous studies suggest that aortic remodeling continues after AngII infusion is completed with continued increases in proteolytic enzymes and inflammation. 36,37 Continued infusion of AngII is required for sustained increase in blood pressure, although previous studies suggest that AAA promoting properties of AngII are distinct to those stimulating hypertension. 38 In a recent study, we found that blood pressure immediately dropped when AngII infusion ceased at day 28 and returned to baseline by day 42; however, the aortic diameter continued to expand.…”

mentioning

confidence: 99%

A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

Krishna

Seto

Jose

et al. 2015

ATVB

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This activation was observed to be dependent on the interaction between a specific TSP-1 sequence (lysine-argininephenylalanine-lysine; KRFK) and a conserved sequence (leucine-serine-lysine-leucine [LSKL]) near the amino terminus in the latency-associated peptide.14 The lysine--arginine-phenylalanine-lysine sequence interacts with the © 2014 American Heart Association, Inc.Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.114.304732Objective-Interaction of the activating sequence in thrombospondin-1 (TSP-1) with the conserved sequence (leucine-serinelysine-leucine [LSKL]) in the latency-associated peptide region of latent transforming growth factor (TGF)-β complex is important in regulating TGF-β1 activity. We aimed to assess the effect of blocking peptide LSKL on the progression of pre-established abdominal aortic aneurysm in angiotensin II-infused apolipoprotein E-deficient (ApoE −/− ) mice. Approach and Results-Abdominal aortic aneurysm was established in 3-month-old male ApoE −/− mice with subcutaneous infusion of angiotensin II for 28 days. After this, mice received LSKL peptide or control SLLK (serine-leucine-leucinelysine) peptide (4 mg/kg) via daily intraperitoneal injection for an additional 2 weeks. Administration of LSKL peptide promoted larger suprarenal aortic diameter, as determined by ultrasound and morphometric analysis, and stimulated more severe atherosclerosis within the aortic arch. In addition, mice receiving LSKL peptide exhibited elevated circulating proinflammatory cytokine levels and greater inflammatory cells within the suprarenal aorta compared with controls. Mice receiving LSKL peptide showed low plasma TGF-β1 activity and low levels of aortic tissue phosphorylated to total Smad2/3. Aortic gene expression of TGF-β receptor 1 (TGFBRI) and receptor 2 (TGFBRII), but not TGF-β1 and thrombospondin-1, were lower in mice receiving LSKL peptide than controls. LSKL peptide administration was associated with greater aortic elastin fragmentation and lower expression and activity of the TGF-β1-target gene lysyl oxidase like 1 (LOXL1). LSKL sequence to displace the latency-associated peptide and make the TGF-β1 accessible to its receptors, TGFBR I and II. 15 Previous studies have indicated that the conserved sequence (LSKL) is required for activation of TGF-β1 and that mimetic peptides of the sequence act as selective antagonists of TSP-1-mediated TGF-β1 activation in vitro and in vivo. [16][17][18] Previous reports suggest that LSKL peptide-mediated attenuation of TGF-β1 activation can prevent the progression of cardiac, hepatic, and renal interstitial fibrosis. 15,17,19 Complete deficiency of TGF-β1 pathway proteins has marked pathological effects, leading to in utero death. Conclusions-Attenuation 20,21Because TSP-1 provides only one of the means by which TGF-β1 is activated, targeting this protein could have clinical relevance as a less severe strategy with potential to be applied to patients. [22][23][24][25] We are aware of no previous studies whi...

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“…67 In hypercholesterolaemic mice, angiotensin II infusion induces medial dissection of the aorta proximal to aortic branch points, with subsequent formation of suprarenal aortic aneurysms, which can be prevented with the use of ACE-Is. 68 …”

Section: The Role Of the Renin-angiotensin Systemmentioning

confidence: 99%

“…67,68,96,97 For example, infusion of angiotensin II induces suprarenal post-dissection aneurysm formation in animal models and continued infusion has been shown to cause pathological changes in the aneurysmal tissue including infiltration of macrophages and disruption of elastin in the medial layer. 98 The discrepancies between animal and human studies may reflect the challenges of conducting RCTs in AAA patients, including accurately measuring AAA growth and bias in patient recruitment, but may more likely reflect differential associations and physiology across species or differences in the pathology of these aneurysms between humans and artificial animal models.…”

Section: Adverse Eventsmentioning

confidence: 99%

An evaluation of the effect of an angiotensin-converting enzyme inhibitor on the growth rate of small abdominal aortic aneurysms: a randomised placebo-controlled trial (AARDVARK)

Kiru

Bicknell

Falaschetti

et al. 2016

Health Technol Assess

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BACKGROUND: Although data are inconsistent, angiotensin-converting enzyme inhibitors (ACE-Is) have been associated with a reduced incidence of abdominal aortic aneurysm (AAA) rupture in analysis of administrative databases. OBJECTIVES: (1) To investigate whether or not the ACE-I perindopril (Coversyl arginine, Servier) reduces small AAA growth rate and (2) to evaluate blood pressure (BP)-independent effects of perindopril on small AAA growth and to compare the repeatability of measurement of internal and external aneurysm diameters. DESIGN: A three-arm, multicentre, single-blind, randomised placebo-controlled trial. SETTING: Fourteen hospitals in England. PARTICIPANTS: Men or women aged ≥ 55 years with an AAA of 3.0-5.4 cm in diameter by internal or external measurement according to ultrasonography and who met the trial eligibility criteria. INTERVENTIONS: Patients were randomised to receive 10 mg of perindopril arginine daily, 5 mg of the calcium channel blocker amlodipine daily or placebo daily. MAIN OUTCOME MEASURES: The primary outcome was AAA diameter growth using external measurements in the longitudinal plane, which in-trial studies suggested was the preferred measure. Secondary outcome measures included AAA rupture, AAA repair, modelling of the time taken for the AAA to reach the threshold for intervention (5.5 cm) or referral for surgery, tolerance of study medication (measured by compliance, adverse events and quality of life) and a comparison of the repeatability of measures of internal and external AAA diameter. Patients were followed up every 3-6 months over 2 years. RESULTS: In total, 227 patients were recruited and randomised into the three groups, which were generally well matched at baseline. Multilevel modelling was used to determine the maximum likelihood estimates for AAA diameter growth. No significant differences in the estimates of annual growth were apparent [1.68 (standard error 0.02) mm, 1.77 (0.02) mm and 1.81 (0.02) mm in the placebo, perindopril and amlodipine groups, respectively]. Similarly, no significant differences in the slopes of modelled growth over time were apparent between perindopril and placebo (p = 0.78) or between perindopril and amlodipine (p = 0.89). The results were essentially unaffected by adjustment for potential confounders. Compliance, measured by pill counts, was good throughout (> 80% at all visit time points). There were no significant in-trial safety concerns. Six patients withdrew because of adverse events attributed to the study medications (n = 2 perindopril, n = 4 amlodipine). No patients ruptured their AAA and 27 underwent elective surgery during the trial (n = 9 placebo, n = 10 perindopril, n = 8 amlodipine). CONCLUSIONS: We were unable to demonstrate a significant impact of perindopril compared with placebo or amlodipine on small AAA growth over a 2-year period. Furthermore, there were no differences in the times to reach a diameter of 5.5 cm or undergo surgery among the three groups. Perindopril and amlodipine were well tolerated by this population. ...

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Involvement of Vascular Angiotensin II-Forming Enzymes in the Progression of Aortic Abdominal Aneurysms in Angiotensin II- Infused ApoE-Deficient Mice

Cited by 33 publications

References 36 publications

TGF-β in the pathogenesis and prevention of disease: a matter of aneurysmic proportions

TGF-β in the pathogenesis and prevention of disease: a matter of aneurysmic proportions

A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

An evaluation of the effect of an angiotensin-converting enzyme inhibitor on the growth rate of small abdominal aortic aneurysms: a randomised placebo-controlled trial (AARDVARK)

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