Persistence of the Nitric Oxide Pathway in the Aorta of Hypercholesterolemic Apolipoprotein-E-Deficient Mice

Villeneuve, Nicole; Fortuño, Ana; Sauvage, Marie; Fournier, Nancy; Breugnot, Christine; Jacquemin, Christine; Petit, Christine; Gosgnach, Willy; Carpentier, Nathalie; Vanhoutte, Paul M.; Vilaine, Jean‐Paul

doi:10.1159/000070705

Cited by 19 publications

(20 citation statements)

References 31 publications

(33 reference statements)

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“…4,5 Although endothelial dysfunction has been considered one of the early steps in atherosclerosis, 1 a normal endothelial function of the aorta was reported recently in apoE mice at 35 weeks of age. 9 In the present study, we evaluated the endothelial function of resistance vessels in young (10 to 12 weeks old) apoE mice and also observed a normal endothelial function. The main candidates that could explain the normal endothelial function in apoE fed with a normal chow diet would be the overexpression of NO synthase or an increased production of superoxide dismutase and catalase enzymes.…”

Section: Discussionmentioning

confidence: 86%

“…4,5 In this experimental model, an endothelial dysfunction has been reported under a Western-type cholesterol-rich diet 6 -8 but not under a normal chow diet. 9 Arterial hypertension has also been associated with changes in endothelial function and in vascular smooth muscle cell reactivity to contractile agents. 10 In addition, arterial hypertension induced by endogenous or administered angiotensin II aggravates the atherosclerotic process in apoE mice.…”

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confidence: 99%

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Evaluation of Vascular Function in Apolipoprotein E Knockout Mice With Angiotensin-Dependent Renovascular Hypertension

et al. 2005

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Abstract-It is known that the endothelial function is compromised in atherosclerosis and arterial hypertension and that angiotensin is an important factor contributing to both pathophysiologies. The aim of this study was to evaluate the vascular function in a hypercholesterolemia/atherosclerosis model, in the angiotensin II-dependent 2-kidney 1-clip (2K1C) hypertension model and when both conditions coexist. Eight-week-old apolipoprotein E knockout (apoE; nϭ20) and C57BL/6 (C57; nϭ20) mice underwent a 2K1C or sham operation and were studied 28 days later. Mean arterial pressure was higher in apoE-2K1C and C57-2K1C (126Ϯ3 and 128Ϯ3 mm Hg) when compared with the apoE-Sham and C57-Sham (103Ϯ2 and 104Ϯ2 mm Hg, respectively; PϽ0.05). The vascular reactivity to norepinephrine (NE; 10 Ϫ9to 2ϫ10 Ϫ3 mol/L), acetylcholine (ACh), and sodium nitroprusside (SNP; 10 Ϫ10 to 10 Ϫ3 mol/L) was evaluated in the mesenteric arteriolar bed through concentration-effect curves. NE caused vascular hyper-reactivity in apoE-Sham, apoE-2K1C, and C57-2K1C (maximal response 146Ϯ5, 144Ϯ5, and 159Ϯ4 mm Hg, respectively) compared with C57-Sham (122Ϯ7 mm Hg; PϽ0.05). The ACh-induced relaxation was smaller (PϽ0.05) in apoE-2K1C and C57-2K1C (maximal response 53Ϯ3% and 46Ϯ3%) than in apoE-Sham and C57-Sham mice (78Ϯ5% and 73Ϯ4%). SNP-induced vascular relaxation showed similar concentration-effect curves in all groups. We conclude that in C57-2K1C mice, the increased reactivity to NE and the decreased endothelium-dependent relaxation contribute to the maintenance of hypertension. The apoE mouse, at early stages of atherosclerosis, shows hyper-reactivity to NE but does not have endothelium dysfunction yet. However, the concurrence of both pathophysiologies does not result in additive effects on the vascular function. Key Words: atherosclerosis Ⅲ mice Ⅲ hypertension, renovascular Ⅲ apolipoproteins Ⅲ mesenteric arteries Ⅲ mice A therosclerosis and arterial hypertension are multifactorial diseases recognized as the main causes of acute cardiovascular events. These pathophysiologies are characterized by endothelial dysfunction, 1,2 and angiotensin II seems to be involved in both diseases. 3 Over the past decades, the availability of new investigative tools, including the homozygous apolipoprotein E knockout (apoE) mouse, has contributed to the understanding of the atherosclerotic process. ApoE is a constituent of VLDL synthesized by the liver and mediates high-affinity binding of apoEcontaining lipoprotein particles to LDL receptors, and thus is responsible for the cellular uptake of these particles. 4 Therefore, apoE mice develop marked hypercholesterolemia and spontaneous atherosclerosis. 4,5 In this experimental model, an endothelial dysfunction has been reported under a Western-type cholesterol-rich diet 6 -8 but not under a normal chow diet. 9 Arterial hypertension has also been associated with changes in endothelial function and in vascular smooth muscle cell reactivity to contractile agents. 10 In addition, arterial hypertension induced by endoge...

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Section: Discussionmentioning

confidence: 86%

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confidence: 99%

Evaluation of Vascular Function in Apolipoprotein E Knockout Mice With Angiotensin-Dependent Renovascular Hypertension

et al. 2005

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“…The investigator was blinded to genotype or treatment for all experiments, and endothelial vasorelaxation was studied as described previously (45)(46)(47)(48). Thoracic aortas from the indicated mice were carefully excised and quickly immersed in Krebs Henseleit solution (118 mM NaCl, 5.4 mM KCl, 1.2 mM MgCl2, 2.5 mM CaCl2, 22 mM NaHCO3, 1.2 mM NaH2PO4, and 10.1 mM glucose) aerated with 95% O2 and 5% CO2 (37°C, pH 7.4).…”

Section: Methodsmentioning

confidence: 99%

Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE–/– mice

et al. 2008

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Endothelial dysfunction is a key triggering event in atherosclerosis. Following the entry of lipoproteins into the vessel wall, their rapid modification results in the generation of advanced glycation endproduct epitopes and subsequent infiltration of inflammatory cells. These inflammatory cells release receptor for advanced glycation endproduct (RAGE) ligands, specifically S100/calgranulins and high-mobility group box 1, which sustain vascular injury. Here, we demonstrate critical roles for RAGE and its ligands in vascular inflammation, endothelial dysfunction, and atherosclerotic plaque development in a mouse model of atherosclerosis, apoE -/-mice. Experiments in primary aortic endothelial cells isolated from mice and in cultured human aortic endothelial cells revealed the central role of JNK signaling in transducing the impact of RAGE ligands on inflammation. These data highlight unifying mechanisms whereby endothelial RAGE and its ligands mediate vascular and inflammatory stresses that culminate in atherosclerosis in the vulnerable vessel wall.

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“…9,60,64 -66 Vascular expression of CuZn-SOD and Mn-SOD mRNA change in a temporal pattern during atherosclerosis (initially increase, then decrease over time). 67,68 There is a marked increase in Mn-SOD expression in cerebral arteries in bacterial meningitis, 69 and Mn-SOD expression is increased in the vessel wall in models of chronic hypertension. 53,54,70 In nonvascular tissue, Ang II increases levels of Mn-SOD protein but also decreases activity of MnSOD caused by peroxynitrite-induced tyrosine protein nitration.…”

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confidence: 99%

Vascular Protection

Faraci

Didion

2004

ATVB

412

204

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Abstract-Blood vessels express 3 isoforms of superoxide dismutase (SOD): cytosolic or copper-zinc SOD (CuZn-SOD), manganese SOD (Mn-SOD) localized in mitochondria, and an extracellular form of CuZn-SOD (EC-SOD). Because there are no selective pharmacological inhibitors of individual SOD isoforms, the functional importance of the different SODs has been difficult to define. Recent molecular approaches, primarily the use of genetically-altered mice and viral-mediated gene transfer, have allowed investigators to begin to define the role of specific SOD isoforms in vascular biology. This review will focus mainly on the role of individual SODs in relation to endothelium under normal conditions and in disease states. This area is important because reactive oxygen species and superoxide anion are thought to play major roles in changes in vascular structure and function in pathophysiology. Key Words: reactive oxygen species Ⅲ endothelium Ⅲ nitric oxide Ⅲ superoxide dismutase Ⅲ peroxynitrite S uperoxide anion (O 2 Ϫ ) and other reactive oxygen species (ROS) play a major role in vascular biology. In general, relatively low concentrations of ROS are thought to act as mediators or modulators of cell signaling and contribute to other key functions, such as regulation of activity of transcription factors and gene expression. [1][2][3] In contrast, higher levels of ROS contribute to vascular dysfunction and abnormal cell growth including hypertrophy of vascular muscle. Superoxide levels are increased in blood vessels in many pathophysiological conditions including hypertension, atherosclerosis, diabetes, hyperhomocysteinemia, heart failure, sepsis, subarachnoid hemorrhage, and Alzheimer disease, as well as during aging. Since the initial evidence that superoxide or other ROS inactivate nitric oxide (NO) or endothelium-derived relaxing factor (EDRF), 4 many studies have suggested that inactivation of NO by superoxide contributes to vascular dysfunction under pathophysiological conditions. Steady-state levels of superoxide are dependent on both its rate of production as well as activity of the various superoxide dismutases (SODs). The goal of this review is to briefly summarize the role of SODs in relation to vascular biology with an emphasis on endothelium. This summary will mainly focus on highlighting recent work from an emerging field, the functional importance of specific SOD isoforms in vascular protection. Superoxide Dismutases: Basic Characteristics and FunctionsIn mammals, there are 3 isoforms of SOD, 5 and each are products of distinct genes but catalyze the same reaction: As indicated above, SODs dismute superoxide into hydrogen peroxide plus molecular oxygen. There are several functional consequences of this enzymatic activity. First, SODs protect against superoxide-mediated cytotoxicity, such as inactivation of mitochondrial proteins containing ironsulfur (Fe-S) centers (eg, aconitase and fumarase) ( Figure 2). 5 Such interactions are of potential importance, as damage to such complexes results in release of free i...

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Persistence of the Nitric Oxide Pathway in the Aorta of Hypercholesterolemic Apolipoprotein-E-Deficient Mice

Cited by 19 publications

References 31 publications

Evaluation of Vascular Function in Apolipoprotein E Knockout Mice With Angiotensin-Dependent Renovascular Hypertension

Evaluation of Vascular Function in Apolipoprotein E Knockout Mice With Angiotensin-Dependent Renovascular Hypertension

Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE–/– mice

Vascular Protection

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