The influence of angiotensin-converting enzyme inhibitors on the aorta elastin metabolism in diet-induced hypercholesterolaemia in rabbits

Wojakowski, Wojciech; Gmiński, Jan; Siemianowicz, Krzysztof; Goss, M; Machalski, M

doi:10.3317/jraas.2001.006

Cited by 12 publications

(8 citation statements)

References 42 publications

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“…Although these results seem to be at odds with effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers to limit ECM deposition in nonatherogenic disorders, they echo observations made in other models of atherosclerosis, including the Watanabe heritable hyperlipidemic rabbits and atherosclerotic mini-pigs, in which angiotensin-converting enzyme inhibitors/angiotensin receptor blockers increased ECM, including collagen, in the aortas. 29,34 These findings complement recent observations that remodeling pathways may be tissue specific. Plasminogen activator inhibitor-1 deficiency was shown to protect against combined AngII and aldosterone-induced remodeling in the aortas but enhance AngII and aldosterone as well as senescent fibrosis in the heart.…”

Section: Discussionsupporting

confidence: 78%

“…It is interesting that AngII antagonism prevented an increase in serum and aortic elastolytic activity in cholesterol-fed rabbits and ameliorated arterial internal lamina ruptures in Brown Norway rats. 34,39 Although elastin per se has been identified as a pivotal modulator of vascular response to injury, previous studies focused on macrophage-related elastolytic proteases. 40,41 This study makes the novel observations that AngII increases elastolysis by SMC in vitro and elastin breaks in the aortic media in vivo, although a contribution from macrophages and/or endothelial cells cannot be completely excluded.…”

Section: Discussionmentioning

confidence: 99%

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Angiotensin Inhibition Decreases Progression of Advanced Atherosclerosis and Stabilizes Established Atherosclerotic Plaques

Suganuma¹,

Babaev²,

Motojima³

et al. 2007

Journal of the American Society of Nephrology

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Although increased extracellular matrix (ECM) is pathogenic in a variety of chronic tissue injuries, reduced and/or disrupted ECM may be detrimental in atherosclerosis and rather destabilize existing atherosclerotic lesions. This study therefore assessed the effects of angiotensin II (AngII) antagonism on ECM components of advanced atherosclerosis. Twenty-four-week-old apolipoprotein E-deficient mice were treated with the AngII antagonist losartan for 12 wk. Controls received water or hydralazine. AngII antagonism significantly reduced progression of established atherosclerosis, whereas hydralazine showed no benefit despite similar decrease in BP. Although there was no difference in the macrophage component, AngII antagonism increased the relative collagen portion of the lesions; lessened elastin fragmentation, increased the total elastin content of the aorta; and reduced the mRNA and activity/ protein of the elastolytic proteases, cathepsin S, and metalloproteinase-9. Extracellular elastin degradation by cultured smooth muscle cells (SMC) was reduced by losartan, as was SMC invasion through an elastin gel barrier. Thus, AngII antagonism lessens progression of atherosclerosis, increases collagen, and preserves elastin components of ECM within the vascular lesions, which, at least in part, is modulated by effects on SMC. These effects not only decrease further expansion of advanced lesions but also stabilize the established atherosclerotic plaques and may underlie the decreased incidence of acute cardiovascular events that are observed in patients in whom AngII antagonism is begun after atherosclerosis is already established.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Angiotensin Inhibition Decreases Progression of Advanced Atherosclerosis and Stabilizes Established Atherosclerotic Plaques

Suganuma¹,

Babaev²,

Motojima³

et al. 2007

Journal of the American Society of Nephrology

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“…Our study reveals that UNx per se dramatically increases elastin damage, evidenced by almost doubling in the number of breaks in the elastin lamellae found in UNx mice compared with shams. Losartan but not hydralazine treatment completely abrogated this effect and reiterates previously noted elastolytic properties of Ang II (47). The effects on elastin damage dissociated from UNx effects on the medial area, which was similar in sham and UNx, and decreased similarly with losartan and hydralazine treatment.…”

Section: Discussionsupporting

confidence: 55%

Antiatherogenic Effects of Angiotensin Receptor Antagonism in Mild Renal Dysfunction

Suganuma

Zuo

Ayabe

et al. 2006

Journal of the American Society of Nephrology

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Angiotensin II (Ang II) increases atherosclerotic cardiovascular disease. Renal damage that is characterized by activation of Ang II markedly potentiates the risk for atherosclerosis, even in the setting of subtle renal impairment. Therefore, whether antagonism of Ang II actions can modify atherosclerosis in a model of mild renal impairment was examined. Apolipoprotein E-deficient spontaneously hyperlipidemic mice underwent uninephrectomy (UNx) or sham operation (sham) followed by treatment with Ang II receptor antagonist losartan or hydralazine for 12 wk. While UNx did not increase the serum creatinine levels, BP and lipids were higher in UNx mice than in age-matched sham controls with intact kidneys. UNx caused a dramatic increase in the extent and the number of atherosclerotic lesions together with greater macrophage-positive area and more disruption in the elastin component of the extracellular matrix versus sham. Ang II antagonism dramatically decreased the UNx-induced acceleration in atherosclerosis in association with decreased macrophage content, linked to decreased macrophage migration in vitro with losartan but not with hydralazine. Aortae of mice treated with Ang II antagonism had fewer elastin breaks together with less immunostaining for the powerful elastolytic enzyme cathepsin S. None of these benefits was observed in the hydralazine-treated mice despite equivalent reduction in BP. These findings support an important role for endogenous Ang II in accelerated atherosclerosis in renal dysfunction and offer a therapeutic intervention with particular benefit in this setting through mechanisms that include reduced vascular macrophage infiltration and preservation of the elastin component of extracellular matrix.

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“…35 Angiotensin II stimulates both myocardial and vascular collagen expression, 36 and previous studies have demonstrated that interruption of the renin-angiotensin system decreases collagen deposition 37,38 and/or increases the elastin/collagen ratio. [11][12][13]38,39 These previous in vivo animal ACE inhibition studies have not, however, examined such effects independently of changes in hemodynamics. The current cell culture data indicate that ramipril increased deposition of elastic components of the extracellular matrix, including fibrillin-1 and elastin, while reducing collagen deposition.…”

Section: Mechanismsmentioning

confidence: 99%

“…9,10 ACE inhibitors have been shown to increase the elastin to collagen ratio in a number of disease models. [11][12][13] Though of great interest, the relevance of these animal models to humans is unknown. Furthermore, these chronic studies cannot specifically examine the direct effects of ACE inhibitors on arterial matrix protein deposition independently of their hemodynamic actions.…”

mentioning

confidence: 99%

Ramipril Reduces Large-Artery Stiffness in Peripheral Arterial Disease and Promotes Elastogenic Remodeling in Cell Culture

et al. 2005

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Abstract-Ramipril improves cardiovascular outcome in patients with peripheral arterial disease; however, the precise mechanisms of benefit remain to be elucidated. The effect of ramipril on large-artery stiffness in patients with peripheral arterial disease was examined. In addition, we determined the effect of ramiprilat on extracellular matrix from human aortic smooth muscle cell culture. Forty patients with peripheral arterial disease were randomized to receive ramipril, 10 mg once daily or placebo for 24 weeks. Arterial stiffness was assessed globally via systemic arterial compliance and augmentation index (carotid tonometry and Doppler velocimetry), and regionally via carotid-femoral pulse wave velocity. Angiotensin-converting enzyme inhibition increased arterial compliance by 0.10Ϯ0.02 mL/mm Hg, (PϽ0.001, all probability values relative to placebo) and reduced pulse wave velocity by 1.7Ϯ0.2 m/s (PϽ0.001), augmentation index by 4.1Ϯ0.3% (PϽ0.001), and systolic blood pressure by 5Ϯ1 mm Hg (PϽ0.001). Ramipril did not reduce mean arterial pressure significantly compared with placebo (Pϭ0.59). In cell culture, ramiprilat decreased collagen deposition by Ͼ50% and increased elastin and fibrillin-1 deposition by Ͼ3-and 4-fold respectively (histochemistry and immunohistochemistry). Fibrillin-1 gene expression was increased 5-fold (real-time reverse-transcriptase polymerase chain reaction). Ramiprilat also reduced gene and protein (Western) expression of both matrix metalloproteinase (MMP)-2 and MMP-3. In conclusion, ramipril promoted an elastogenic matrix profile that may contribute to the observed clinical reduction in large-artery stiffness and carotid pressure augmentation, which occurred independently of mean arterial blood pressure reduction in patients with peripheral arterial disease.

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The influence of angiotensin-converting enzyme inhibitors on the aorta elastin metabolism in diet-induced hypercholesterolaemia in rabbits

Abstract: Aortic elastin turnover is significantly accelerated in atherosclerosis, partly because of activation of the renin-angiotensin-aldosterone system caused by hypercholesterolaemia. We postulated that angiotensinconverting enzyme inhibitors (ACE

Cited by 12 publications

References 42 publications

Angiotensin Inhibition Decreases Progression of Advanced Atherosclerosis and Stabilizes Established Atherosclerotic Plaques

Angiotensin Inhibition Decreases Progression of Advanced Atherosclerosis and Stabilizes Established Atherosclerotic Plaques

Antiatherogenic Effects of Angiotensin Receptor Antagonism in Mild Renal Dysfunction

Ramipril Reduces Large-Artery Stiffness in Peripheral Arterial Disease and Promotes Elastogenic Remodeling in Cell Culture

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