Deletion of angiotensin-converting enzyme 2 promotes the development of atherosclerosis and arterial neointima formation

Sahara, Makoto; Ikutomi, Masayasu; Morita, Toshihiro; Minami, Yoshiyasu; Nakajima, Toshiaki; Hirata, Yasunobu; Nagai, Ryozo; Sata, Masataka

doi:10.1093/cvr/cvt245

Cited by 69 publications

(58 citation statements)

References 35 publications

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“…The observed pronounced increase in Ang I, Ang II, Ang III and Ang IV but not Ang-(1-7) suggests activation of renin as well as increase in ACE/ACE2 activity ratio. Our results appear to be consistent with the known pro-atherogenic role of renin [32,33] and ACE [34,35] as well as anti-atherogenic activity of ACE2 [36][37][38]. Which of the three culprits: renin, ACE or ACE2 is the major contributor to the development of atherogenesis, or whether they all play in concert, remains to be established.…”

Section: Analytesupporting

confidence: 88%

“…Which of the three culprits: renin, ACE or ACE2 is the major contributor to the development of atherogenesis, or whether they all play in concert, remains to be established. Surprisingly, despite the intense interest in the role of angiotensin peptides in atherogenesis, there are only few earlier studies attempted to describe the angiotensin distribution/concentrations in atherosclerotic mouse models [8,13,36].…”

Section: Analytementioning

confidence: 99%

See 1 more Smart Citation

Development of a sensitive, accurate and robust liquid chromatography/mass spectrometric method for profiling of angiotensin peptides in plasma and its application for atherosclerotic mice

Olkowicz

Radulska

Suraj³

et al. 2015

Journal of Chromatography A

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Section: Analytesupporting

confidence: 88%

Section: Analytementioning

confidence: 99%

Development of a sensitive, accurate and robust liquid chromatography/mass spectrometric method for profiling of angiotensin peptides in plasma and its application for atherosclerotic mice

Olkowicz

Radulska

Suraj³

et al. 2015

Journal of Chromatography A

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“…The protective action of ACE2 on atherosclerosis is also supported by data on ACE2-deficient mice model. ACE2-deficiency in both low-density lipoprotein receptor-deficient (Ldlr −/− ) and ApoE −/− backgrounds presented larger atherosclerotic lesions when compared to their respective controls [23–25]. In the present study, three weeks of treatment with diminazene did not alter the atherosclerotic lesion size.…”

Section: Discussioncontrasting

confidence: 43%

“…Indeed, ACE2 overexpression attenuates the progression of atherosclerotic lesions and increases plaque stability [22]. Contrarily, ACE2 deficiency in low-density lipoprotein receptor (Ldlr −/− ) or apolipoprotein E (ApoE −/− )-deficient mice worsens atherogenesis [23–25]. Based on these observations, ACE2 has being suggested as a potential target for the treatment of atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

Diminazene enhances stability of atherosclerotic plaques in ApoE-deficient mice

Fraga‐Silva

Montecucco

Costa‐Fraga

et al. 2015

Vascular Pharmacology

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Angiotensin (Ang) II contributes to the development of atherosclerosis, while Ang-(1–7) has atheroprotective actions. Accordingly, angiotensin-converting enzyme 2 (ACE2), which breaks-down Ang II and forms Ang-(1–7), has been suggested as a target against atherosclerosis. Here we investigated the actions of diminazene, a recently developed ACE2 activator compound, in a model of vulnerable atherosclerotic plaque. Atherosclerotic plaque formation was induced in the carotid artery of ApoE-deficient mice by a shear stress (SS) modiffer device. The animals were treated with diminazene (15 mg/kg/day) or vehicle. ACE2 was strongly expressed in the aortic root and low SS-induced carotid plaques, but poorly expressed in the oscillatory SS-induced carotid plaques. Diminazene treatment did not change the lesion size, but ameliorated the composition of aortic root and low SS-induced carotid plaques by increasing collagen content and decreasing both MMP-9 expression and macrophage infiltration. Interestingly, these beneficial effects were not observed in the oscillatory SS-induced plaque. Additionally, diminazene treatment decreased intraplaque ICAM-1 and VCAM-1 expression, circulating cytokine and chemokine levels and serum triglycerides. In summary, ACE2 was distinctively expressed in atherosclerotic plaques, which depends on the local pattern of shear stress. Moreover, diminazene treatment enhances the stability of atherosclerotic plaques.

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“…Abdominal aorta segments transfected with AdACE2 showed a delayed onset of atherosclerotic lesions with fewer macrophages, less lipid deposition, more collagen contents, decreased expression of Ang II, MCP-1, LOX-1 and increased angiotensin (1-7) levels in plaque tissue [116]. In two different models of vascular disease, both hyperlipidaemia-induced atherosclerosis in ApoE-/-mice and mechanical injury-induced arterial neointimal hyperplasia in C57Bl6 mice, ACE2 deficiency resulted in significantly larger vascular lesions and neointimal hyperplasia compared with ACE2(+) controls [117]. ACE2 and exogenous Ang-(1-7) significantly inhibit early atherosclerotic lesion formation by preserving endothelial function and inhibiting of an inflammatory response in ApoE-/-mice [118,119].…”

Section: Main Ras Molecules In Atherosclerosis Through the Magnifyingmentioning

confidence: 99%

Involvement of the Renin‐Angiotensin System in Atherosclerosis

Kolaković¹,

Živković²,

Stanković³

2017

Renin-Angiotensin System - Past, Present and Future

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The renin-angiotensin system (RAS) is a well known for its role in the regulation of the blood pressure (BP). Angiotensin II (Ang II), the main mediator of the RAS, may act either, as a systemic molecule or a locally produced factor. Within the vessel wall it has significant proinflammatory role by inducing the oxidative stress, secretion of inflammatory cytokines and adhesion molecules. Ang II could trigger proliferation of vascular smooth muscle cells (VSMC) and its migration to the outer layer of the vessel wall. It could induce the release of matrix metalloproteinase (MMPs), from human VSMC and thus increase susceptibility to rupture of atherosclerotic lesions. Binding of Ang II to AT1R/AT2R could have opposing actions in vascular injury. The ACE2/Ang (1-7)/Mas axis of the RAS also opposes the unfavourable actions of ACE/Ang II/ATR1 axis. Inhibition of RAS could reduce inflammation-associated processes in vasculature, independently of lowering BP. RAS is significantly modulated by the genes coding for this system. Certain genetic variants (SNPs) in the RAS genes have been denoted as the functional ones and have been associated with hypertension, cardiovascular phenotypes and atherosclerosis. Also, the genetic components of the RAS interfere with the regulators of gene expression by microRNAs (miRs).

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Deletion of angiotensin-converting enzyme 2 promotes the development of atherosclerosis and arterial neointima formation

Abstract: ACE2 deficiency promotes the development of vascular diseases associated with Ang-II-mediated vascular inflammation and activation of the JNK signalling, leading to the notion that ACE2 potentially confers protection against vascular diseases.

Cited by 69 publications

References 35 publications

Development of a sensitive, accurate and robust liquid chromatography/mass spectrometric method for profiling of angiotensin peptides in plasma and its application for atherosclerotic mice

Development of a sensitive, accurate and robust liquid chromatography/mass spectrometric method for profiling of angiotensin peptides in plasma and its application for atherosclerotic mice

Diminazene enhances stability of atherosclerotic plaques in ApoE-deficient mice

Involvement of the Renin‐Angiotensin System in Atherosclerosis

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