Angiotensin II infusion in man is proinflammatory but has no short-term effects on thrombin generation in vivo

Ekholm, Mikael; Kahan, Thomas; Jörneskog, Gun; Bröijersén, Anders; Wallén, N H

doi:10.1016/j.thromres.2008.12.040

Cited by 25 publications

(40 citation statements)

References 30 publications

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“…Most research has focused on the pro-oxidant and proinflammatory actions of Ang II, which promotes monocyte and endothelial cell activation 29 and ultimately plaque accumulation. 30 Increasing levels of aldosterone associated with renin-angiotensin system activation may also have direct atherogenic effects in apoE KO mice.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Renin-Angiotensin System Mediates the Effects of Dietary Salt Intake on Atherogenesis in the Apolipoprotein E Knockout Mouse

et al. 2012

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Abstract-Dietary salt intake is a major determinant of the activation state of renin-angiotensin-aldosterone system. Given the important role of the renin-angiotensin-aldosterone system in plaque accumulation, we investigated its role in the development of atherogenesis associated with sodium intake in apolipoprotein E knockout mice. Six-weeks of a low-salt diet (containing 0.03% sodium) resulted in a 4-fold increase in plaque accumulation in apolipoprotein E knockout mice when compared with mice receiving normal chow (containing 0.30% sodium). This was associated with activation of the renin-angiotensin-aldosterone system, increased vascular expression of adhesion molecules and inflammatory cytokines, and increased adhesion of labeled leukocytes across the whole aorta on a dynamic flow assay. These changes were blocked with the angiotensin-converting enzyme inhibitor perindopril (2 mg/kg per day). A high-salt diet (containing 3% sodium) attenuated vascular inflammation and atherogenesis, associated with suppression of the renin-angiotensin-aldosterone system, although systolic blood pressure levels were modestly increased (5Ϯ1 mmHg). Constitutive activation of the reninangiotensin-aldosterone system in angiotensin-converting enzyme 2 apolipoprotein E knockout mice was also associated with increased atherosclerosis and vascular adhesion, and this was attenuated by a high-salt diet associated with suppression of the renin-angiotensin-aldosterone system. By contrast, a low-salt diet failed to further activate the renin-angiotensinaldosterone system or to increase atherosclerosis in angiotensin-converting enzyme 2 apolipoprotein E knockout mice. Together, these data validate a relationship between salt-mediated renin-angiotensin-aldosterone system activation and atherogenesis, which may partly explain the inconclusive or paradoxical findings of recent observational studies, despite clear effects on blood pressure. (Hypertension. 2012;60:98-105.)

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Section: Discussionmentioning

confidence: 99%

Activation of the Renin-Angiotensin System Mediates the Effects of Dietary Salt Intake on Atherogenesis in the Apolipoprotein E Knockout Mouse

et al. 2012

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“…Although the pathogenesis of diabetes-associated CVD (cardiovascular disease) is multi-factorial, central among these mediators is activation of the RAS (renin-angiotensin system) in the heart [2][3][4] and in the vasculature [5]. In particular, it is known that AngII (angiotensin II) has a number of direct pro-atherosclerotic effects [6][7][8], whereas blockade of the RAS has anti-atherosclerotic actions [5,9], additional and independent of systemic BP (blood pressure) [5]. Similarly, AngII-dependent signalling in the diabetic heart is associated with oxidative damage, fibrogenesis and myocyte apoptosis [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Interaction of diabetes and ACE2 in the pathogenesis of cardiovascular disease in experimental diabetes

et al. 2012

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Local and systemic AngII (angiotensin II) levels are regulated by ACE2 (angiotensin-converting enzyme 2), which is reduced in diabetic tissues. In the present study, we examine the effect of ACE2 deficiency on the early cardiac and vascular changes associated with experimental diabetes. Streptozotocin diabetes was induced in male C57BL6 mice and Ace2-KO (knockout) mice, and markers of RAS (renin-angiotensin system) activity, cardiac function and injury were assessed after 10 weeks. In a second protocol, diabetes was induced in male ApoE (apolipoprotein E)-KO mice and ApoE/Ace2-double-KO mice, and plaque accumulation and markers of atherogenesis assessed after 20 weeks. The induction of diabetes in wild-type mice led to reduced ACE2 expression and activity in the heart, elevated circulating AngII levels and reduced cardiac Ang-(1-7) [angiotensin-(1-7)] levels. This was associated structurally with thinning of the LV (left ventricular) wall and mild ventricular dilatation, and histologically with increased cardiomyocyte apoptosis on TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) staining and compensatory hypertrophy denoted by an increased cardiomyocyte cross-sectional area. By contrast Ace2-KO mice failed to increase circulating AngII concentration, experienced a paradoxical fall in cardiac AngII levels and no change in Ang-(1-7) following the onset of diabetes. At the same time the major phenotypic differences between Ace2-deficient and Ace2-replete mice with respect to BP (blood pressure) and cardiac hypertrophy were eliminated following the induction of diabetes. Consistent with findings in the heart, the accelerated atherosclerosis that was observed in diabetic ApoE-KO mice was not seen in diabetic ApoE/Ace2-KO mice, which experienced no further increase in plaque accumulation or expression in key adhesion molecules beyond that seen in ApoE/Ace2-KO mice. These results point to the potential role of ACE2 deficiency in regulating the tissue and circulating levels of AngII and their sequelae in the context of diabetes, as well as the preservation or augmentation of ACE2 expression or activity as a potential therapeutic target for the prevention of CVD (cardiovascular disease) in diabetes.

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“…Although a number of factors can promote leukocyte adhesion, there is strong evidence that Ang II is able to promote monocyte and endothelial cell activation. 8 In addition, Ang 1-7, the major product of ACE2 14,15 has a range of antiinflammatory effects, which balance or oppose those of Ang II. 16,17 In-so-far-as deficiency or inhibition of ACE2 increases Ang II levels by reducing the formation of Ang 1-7, we hypothesize that its net effects will be to promote vascular adhesion, and with it, early plaque development.…”

mentioning

confidence: 99%

Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse

Thomas

Pickering

Tsorotes

et al. 2010

Circulation Research

230

219

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Objective: Given the important role of Ang II/Ang 1-7 in atherogenesis, we investigated the impact of ACE2 deficiency on the development of atherosclerosis. Methods and Results:C57Bl6, Ace2 knockout (KO), apolipoprotein E (ApoE) KO and ApoE/Ace2 double KO mice were followed until 30 weeks of age. Plaque accumulation was increased in ApoE/Ace2 double KO mice when compared to ApoE KO mice. This was associated with increased expression of adhesion molecules and inflammatory cytokines, including interleukin-6, monocyte chemoattractant protein-1, and vascular cell adhesion molecule-1, and an early increase in white cell adhesion across the whole aortae on dynamic flow assay. In the absence of a proatherosclerotic (ApoE KO) genotype, ACE2 deficiency was also associated with increased expression of these markers, suggesting that these differences were not an epiphenomenon. ACE inhibition prevented increases of these markers and atherogenesis in ApoE/ACE2 double KO mice. Bone marrow macrophages isolated from Ace2 KO mice showed increased proinflammatory responsiveness to lipopolysaccharide and Ang II when compared to macrophages isolated from C57Bl6 mice. Endothelial cells isolated from Ace2 KO mice also showed increased basal activation and elevated inflammatory responsiveness to TNF-␣. Similarly, selective inhibition of ACE2 with MLN-4760 also resulted in a proinflammatory phenotype with a physiological response similar to that observed with exogenous Ang II (10 ؊7 mol/L). Conclusions: Genetic

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Angiotensin II infusion in man is proinflammatory but has no short-term effects on thrombin generation in vivo

Cited by 25 publications

References 30 publications

Activation of the Renin-Angiotensin System Mediates the Effects of Dietary Salt Intake on Atherogenesis in the Apolipoprotein E Knockout Mouse

Activation of the Renin-Angiotensin System Mediates the Effects of Dietary Salt Intake on Atherogenesis in the Apolipoprotein E Knockout Mouse

Interaction of diabetes and ACE2 in the pathogenesis of cardiovascular disease in experimental diabetes

Genetic Ace2 Deficiency Accentuates Vascular Inflammation and Atherosclerosis in the ApoE Knockout Mouse

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