Protective Effect of Chronic Vitamin C Treatment on Endothelial Function of Apolipoprotein E-Deficient Mouse Carotid Artery

Matsumoto, Takuya; d’Uscio, Livius V.; Eguchi, Daihiko; Aoki, Masahiko; Smith, Leslie; Katušić, Zvonimir S.

doi:10.1124/jpet.103.049163

Cited by 37 publications

(29 citation statements)

References 33 publications

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“…In addition, there are cases in which changes in the mRNA levels differ from the expression or activity of a protein. In the case of eNOS, this discordance has been reported in some animal models of atherosclerosis (46)(47)(48)(49), as noted further in Discussion.…”

Section: Body Weights and Plasma Parametersmentioning

confidence: 82%

“…Since it has long been accepted that oxidative and nitrosative stresses participate in all stages of atherosclerotic lesion development (3,59,60), the increased protein nitration observed in the arterial wall of Ucp2 2/2 mice is consistent with such increased local oxidative stress. Considering the eNOS expression in the endothelia of the two genotypes and in response to the diet, several studies using animal models of atherosclerosis have reported either unchanged or augmented expression of eNOS in atherosclerotic arteries, despite the presence of endothelial dysfunction (46)(47)(48)(49). In addition, while inhibition of eNOS by pharmacological inhibitors or by gene knockout on the apoE 2/2 background has been shown to promote atherogenesis (67)(68)(69)(70), eNOS overexpression showed controversial results.…”

Section: Downloaded Frommentioning

confidence: 99%

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Reduced antioxidant capacity and diet-induced atherosclerosis in uncoupling protein-2-deficient mice

Moukdar

Robidoux

Lyght

et al. 2009

Journal of Lipid Research

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Vascular dysfunction in response to reactive oxygen species (ROS) plays an important role in the development and progression of atherosclerotic lesions. In most cells, mitochondria are the major source of cellular ROS during aerobic respiration. Under most conditions the rates of ROS formation and elimination are balanced through mechanisms that sense relative ROS levels. However, a chronic imbalance in redox homeostasis is believed to contribute to various chronic diseases, including atherosclerosis. Uncoupling protein-2 (UCP2) is a mitochondrial inner membrane protein shown to be a negative regulator of macrophage ROS production. In response to a cholesterolcontaining atherogenic diet, C57BL/6J mice significantly increased expression of UCP2 in the aorta, while mice lacking UCP2, in the absence of any other genetic modification, displayed significant endothelial dysfunction following the atherogenic diet. Compared with wild-type mice, Ucp2 2/2 mice had decreased endothelial nitric oxide synthase, an increase in vascular cell adhesion molecule-1 expression, increased ROS production, and an impaired ability to increase total antioxidant capacity. These changes in Ucp2 2/2 mice were associated with increased aortic macrophage infiltration and more numerous and larger atherosclerotic lesions. These data establish that in the vasculature UCP2 functions as an adaptive antioxidant defense to protect against the development of atherosclerosis in response to a fat and cholesterol diet. Atherosclerosis is a multifactorial chronic vascular disease whose prevalence is increasing worldwide approaching epidemic proportions (1). It is believed that atherosclerosis is initiated by a combination of systemic and local inflammatory events that promote all phases of plaque development and progression (2). Moreover, studies using animal models of atherosclerosis have documented that reactive oxygen species (ROS), which are produced and used by all plaque constituents, serve as one of the drivers of the atherosclerotic process (as reviewed in Refs. 3, 4). Indeed, lesion formation is associated with a collection of events that are regulated by ROS: accumulation of lipid peroxidation products (5, 6), induction of inflammatory/ inflammation-related genes (7), inactivation of nitric oxide (NO) leading to endothelial dysfunction (8, 9), activation of matrix metalloproteinases (10), and increased smooth muscle cell growth (11).As a defense against oxidative stress, most eukaryotic cells are equipped with enzymatic and nonenzymatic mechanisms to neutralize oxidants. These mechanisms have been studied extensively in the heart, and the most important of these include enzymes such as superoxide dismutases (SOD), catalase, and glutathione peroxidase (GPx) (12-15). Under normal conditions, ROS and reactive nitrogen species (RNS) are generated as byproducts of oxidative metabolic activity, but are now appreciated to also serve as signaling molecules in some settings (16)(17)(18)(19). However, under pathophysiological conditions, persis...

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Section: Body Weights and Plasma Parametersmentioning

confidence: 82%

Section: Downloaded Frommentioning

confidence: 99%

Reduced antioxidant capacity and diet-induced atherosclerosis in uncoupling protein-2-deficient mice

Moukdar

Robidoux

Lyght

et al. 2009

Journal of Lipid Research

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“…42,43 In line with this report, most studies in atherosclerotic animal models demonstrate unchanged or even augmented expression of eNOS in atherosclerotic arteries, despite the presence of endothelial dysfunction. [44][45][46][47] A most recent study with human coronary atherectomy specimens showed a higher eNOS gene expression in patients with acute coronary syndromes than those with stable angina. 48 These results suggest that endothelial dysfunction in atherosclerosis, at least at the early disease stage, is not attributable to a decrease in eNOS gene expression.…”

Section: Enos Protein Expression In Atherosclerosismentioning

confidence: 99%

Recent Advances in Understanding Endothelial Dysfunction in Atherosclerosis

Yang

Ming²

2006

Clinical Medicine & Research

172

117

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Over the last two decades, it has become evident that decreased bioavailability of endothelial nitric oxide (NO) produced from endothelial NO synthase (eNOS), referred to as endothelial dysfunction, plays a crucial role in the development and progression of atherosclerosis. Much progress has been made in understanding the mechanisms of decreased endothelial NO bioavailability at the levels of regulation of eNOS gene expression, eNOS enzymatic activity and NO inactivation. Initial studies suggest that increasing eNOS gene expression would improve endothelial NO release in the hope of inhibiting the progression of atherosclerosis. Recent experimental studies, however, do not always support this therapeutic concept and show some evidence that overexpression of eNOS in atherosclerosis may be even harmful for the disease progression.Thus, recent research to improve endothelial function in atherosclerosis has focused on regulation of eNOS enzymatic activity and prevention of NO inactivation by oxidative stress. Since the role of oxidative stress in endothelial NO bioavailability has been reviewed in a large number of comprehensive articles, this article focuses on the relevant regulatory mechanisms of eNOS enzymatic activity that are emerging to play a role in endothelial dysfunction in atherosclerosis.

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“…The analysis of vascular reactivity in rat mesenteric artery segments was performed using arteriography (21). Briefly, experiments were performed on 5-mmlong tertiary branches of mesenteric artery from rats that had been anesthetized with pentobarbital (60 mg/kg ip).…”

Section: Studies Of Vascular Reactivitymentioning

confidence: 99%

Heme oxygenase activity as a determinant of the renal hemodynamic response to low-dose ANG II

Nath

Hernandez

Croatt

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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II causes renal injury through hemodynamic and other effects, and pressor doses of ANG II induce heme oxygenase-1 (HO-1) as a protective response. The present studies examined the hemodynamic effects of more clinically relevant, lower doses of ANG II and the role of HO activity in influencing these effects. Under euvolemic conditions, ANG II increased arterial pressure and renal vascular resistance. ANG II did not induce oxidative stress, inflammation/injury-related gene expression, or proteinuria and did not alter extrarenal vascular reactivity. At these doses, ANG II failed to increase HO-1 or HO-2 mRNA expression or HO activity. Inhibiting HO activity in ANG II-treated rats by tin mesoporphyrin further increased renal vascular resistances, decreased renal blood flow, and blunted the rise in arterial pressure without inducing oxidative stress or altering expression of selected vasoactive/ injury/inflammation-related genes; tin mesoporphyrin did not alter vasorelaxation of mesenteric resistor vessels. We conclude that in this model renal vasoconstriction occurs without the recognized adverse effects of ANG II on glomerular filtration rate, renal blood flow, oxidative stress, vascular reactivity, proteinuria, and injury-related gene expression; renal HO activity is essential in preserving perfusion of the ANG II-exposed kidney. These findings represent an uncommon example wherein function of a stressed organ (by ANG II), but not that of the unstressed organ, requires intact renal HO activity, even when the imposed stress neither induces HO-1 nor HO activity. These findings may be germane to conditions attended by heightened ANG II levels, ineffective renal perfusion, and susceptibility to acute kidney injury. tin mesoporphyrin; ischemia ANG II IS A MAJOR CONTRIBUTOR to chronic kidney disease by virtue of its hemodynamic, proinflammatory, and profibrotic effects. Indeed, agents that interrupt the generation of ANG II and the engagement of ANG II with its receptor comprise a fundamental therapeutic approach in the management of patients with chronic kidney disease (12,20,22). Such therapies, however, reduce but do not abort the progression of chronic kidney disease, and thus complementary strategies that can synergize with these therapies would be of interest. In this regard, a fundamental basis for the injurious effects of ANG II involves the imposition of oxidant stress via NADPH oxidase (35). Studies by us and others have demonstrated that ANG II induces the antioxidant gene heme oxygenase-1 (HO-1) (3, 4, 11) in the kidney in vivo and in vitro and that such induction of HO-1, by virtue of its antioxidant, anti-inflammatory, and vasorelaxant properties (1,2,15,24), is implicated as an adaptive, protective mechanism that can reduce the severity of ANG II-induced renal injury.An established approach employed in studying the pathogenetic basis for ANG II-induced renal injury utilizes the chronic administration of ANG II by osmotic minipumps. Such studies demonstrate that ANG II, so administered, provokes markedly i...

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Protective Effect of Chronic Vitamin C Treatment on Endothelial Function of Apolipoprotein E-Deficient Mouse Carotid Artery

Cited by 37 publications

References 33 publications

Reduced antioxidant capacity and diet-induced atherosclerosis in uncoupling protein-2-deficient mice

Reduced antioxidant capacity and diet-induced atherosclerosis in uncoupling protein-2-deficient mice

Recent Advances in Understanding Endothelial Dysfunction in Atherosclerosis

Heme oxygenase activity as a determinant of the renal hemodynamic response to low-dose ANG II

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