Suppression of experimental abdominal aortic aneurysms in the rat by treatment with angiotensin-converting enzyme inhibitors

Liao, Shixiong; Miralles, Manuel; Kelley, Brian J.; Curci, John A.; Borhani, Martin; Thompson, Robert W.

doi:10.1067/mva.2001.112810

Cited by 139 publications

(101 citation statements)

References 62 publications

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“…Angiotensin II has been implicated in aneurysm formation in atherosclerosis-prone apolipoprotein E-deficient (apoEϪ/Ϫ) mice, 32 and ACE inhibitors suppress aneurysm formation in the elastase-perfused rat aorta. 33 Investigation of the effects of elastase on the Ca 2ϩ mobilization mechanisms of aortic contraction in response to angiotensin II and other vasoconstrictor agonists such as norepinephrine or prostaglandin F2␣ would determine whether the effects of elastase are specific to a particular agonist/receptor or involve effects on postreceptor signaling mechanisms.…”

Section: Perspectivesmentioning

confidence: 99%

Elastase-Induced Suppression of Endothelin-Mediated Ca ²⁺ Entry Mechanisms of Vascular Contraction

Chew¹,

Orshal

Khalil

2003

Hypertension

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Abstract-Abdominal aortic aneurysm (AAA) is associated with increased endothelin (ET-1), both systemically and locally in the aorta. Also, elastase activity is increased in human AAA, and elastase perfusion of the aorta induces aneurysm formation in animal models of AAA. However, whether elastase directly affects the ET-1-induced mechanisms of aortic smooth muscle contraction is unclear. Isometric contraction and 45 Ca 2ϩ influx were measured in aortic strips isolated from male Sprague-Dawley rats and treated with elastase (5 U/mL). To avoid degradation of the extracellular matrix proteins by elastase, experiments were performed in the presence of elastin (10 mg/mL). In normal Krebs solution (2.5 mmol/L Ca 2ϩ ), ET-1 (10 Ϫ7 mol/L) caused contraction of aortic strips that was inhibited by elastase (5 U/mL). The elastase-induced inhibition of ET-1 contraction was slow in onset (4.6Ϯ0.4 minutes), time-dependent, complete in 34Ϯ3 minutes, and reversible. In Ca 2ϩ -free Krebs solution, caffeine (25 mmol/L) caused a small contraction that was not inhibited by elastase, suggesting that elastase does not inhibit Ca 2ϩ release from the intracellular stores. Membrane depolarization by 96 mmol/L KCl, which stimulates Ca 2ϩ entry from the extracellular space, caused a contraction that was inhibited by elastase in a concentration-dependent, time-dependent, and reversible fashion. The reversible inhibitory effects of elastase, particularly in the presence of elastin, suggest that they are not due to dissolution of the extracellular matrix or smooth muscle contractile proteins. Elastase also inhibited ET-1 and KCl-induced

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Section: Perspectivesmentioning

confidence: 99%

Elastase-Induced Suppression of Endothelin-Mediated Ca ²⁺ Entry Mechanisms of Vascular Contraction

Chew¹,

Orshal

Khalil

2003

Hypertension

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“…Inflammation, which is temporally and spatially associated with disruption of the orderly lamellar structure of the aortic media followed by adventitial remodeling and fibrosis, appears to play a fundamental role in the development and progression of AAA. 11,12 The destruction of normally long-lived matrix macromolecules such as elastin has been ascribed to a family of endopeptidases, the MMPs. Pathological vascular remodeling is considered to be mediated by MMPs secreted by invasive macrophages, vascular smooth muscle cells and endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of ets, an essential transcription factor for angiogenesis, to prevent the development of abdominal aortic aneurysm in a rat model

et al. 2005

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The pathophysiology of abdominal aortic aneurysms (AAA) is considered to be complicated. As matrix degradation contributes to the progression of AAA, the destruction and degradation of elastin fibers caused by an increase in matrix metalloproteinases (MMPs) plays a pivotal role in the development of AAA. Although ets, an essential transcription factor for angiogenesis, regulates MMPs, the role of ets in the development of AAA has not yet been clarified. Thus, we evaluated the role of ets in a rat AAA model using a decoy strategy. Transfection of ODN into AAA was performed by transient aortic perfusion of elastase and by wrapping the AAA in a delivery sheet containing decoy ODN. The inhibitory effect of ets decoy ODN on ets binding activity was confirmed by gel mobility shift assay. MMPs expression was decreased in the aorta transfected with ets decoy ODN as compared to scrambled decoy ODN. Also, ultrasound study demonstrated that elastase-induced aneurismal dilation was significantly suppressed by transfection of ets decoy ODN at 4 weeks after treatment as compared to scrambled decoy ODN. Moreover, the destruction of elastin fibers was inhibited in the aorta transfected with ets decoy ODN, accompanied by a reduction of MMPs expression. An inhibitory effect of decoy ODN on MMP expression was confirmed by ex vivo experiments showing that transfection of decoy ODN into an organ culture of human aorta resulted in significant inhibition of the secretion of both MMP-1 and MMP-9. Here, we demonstrated that ets may play a pivotal role in the progression of AAA through the activation of MMPs in a rat model. Ets might be a potential target to develop pharmacotherapy/gene therapy to treat AAA through the inhibition of MMPs.

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“…Moreover, ACEI administration to patients with established AAA increased collagen production in the vascular wall and decreased the arterial wall size (Claridge et al,2004). Liao et al demonstrated that differents ACEI could decreased elastin in AAA independently of their lowering arterial blood pressure effects and without changes in the inflammatory status of the aortic wall (Liao et al,2001). Moreover, Alsac et al have shown that perindopril, an ACEI, is able to reduce aneurysm growth in experimental models not only by changes in elastin levels but also by inhibiting MMPs synthesis (Alsac et al,2011).…”

Section: Angiotensin Converting Enzyme Inhibitors (Acei) and Angiotenmentioning

confidence: 99%

Actual Pharmacological Treatment to Reduce Growth of Small Abdominal Aneurysm

Ducajú¹,

Modrego²,

Farré³

et al. 2011

Diagnosis, Screening and Treatment of Abdominal, Thoracoabdominal and Thoracic Aortic Aneurysms

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Suppression of experimental abdominal aortic aneurysms in the rat by treatment with angiotensin-converting enzyme inhibitors

Cited by 139 publications

References 62 publications

Elastase-Induced Suppression of Endothelin-Mediated Ca ²⁺ Entry Mechanisms of Vascular Contraction

Elastase-Induced Suppression of Endothelin-Mediated Ca ²⁺ Entry Mechanisms of Vascular Contraction

Inhibition of ets, an essential transcription factor for angiogenesis, to prevent the development of abdominal aortic aneurysm in a rat model

Actual Pharmacological Treatment to Reduce Growth of Small Abdominal Aneurysm

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Suppression of experimental abdominal aortic aneurysms in the rat by treatment with angiotensin-converting enzyme inhibitors

Cited by 139 publications

References 62 publications

Elastase-Induced Suppression of Endothelin-Mediated Ca 2+ Entry Mechanisms of Vascular Contraction

Elastase-Induced Suppression of Endothelin-Mediated Ca 2+ Entry Mechanisms of Vascular Contraction

Inhibition of ets, an essential transcription factor for angiogenesis, to prevent the development of abdominal aortic aneurysm in a rat model

Actual Pharmacological Treatment to Reduce Growth of Small Abdominal Aneurysm

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Product

Resources

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Elastase-Induced Suppression of Endothelin-Mediated Ca ²⁺ Entry Mechanisms of Vascular Contraction

Elastase-Induced Suppression of Endothelin-Mediated Ca ²⁺ Entry Mechanisms of Vascular Contraction