Vascular Superoxide Dismutase Deficiency Impairs Endothelial Vasodilator Function Through Direct Inactivation of Nitric Oxide and Increased Lipid Peroxidation

Lynch, Shaina M.; Frei, Balz; Morrow, Jason D.; Roberts, L. Jackson; Xu, Aiming; Jackson, T.; Reyna, Ronald; Klevay, Leslie M.; Vita, Joseph A.; Keaney, John F.

doi:10.1161/01.atv.17.11.2975

Cited by 136 publications

(114 citation statements)

References 37 publications

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“…VEGF has been reported to upregulate the expression of superoxide dismutase, a major superoxide scavenger, in endothelial cells [7]. Moreover, reductions in superoxide dismutase have been reported to inhibit endothelium-dependant relaxation through the inactivation of NO [4]. The pivotal role of the superoxide anion in mitigating responses to acetylcholine is not surprising as reactive oxygen species have long been thought to play a key role in diabetic vascular dysfunction [18,19].…”

Section: Discussionmentioning

confidence: 99%

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Chronic treatment with vascular endothelial growth factor preserves agonist-evoked vascular responses in the streptozotocin-induced diabetic rat

et al. 2006

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Aims/hypothesis: Vascular dysfunction is a hallmark of diabetes mellitus and endothelial dysfunction is considered to be a key early component of vascular dysfunction. Attenuated agonist-evoked responses are considered to be a barometer of endothelial/vascular dysfunction. We sought to determine whether vascular endothelial growth factor (VEGF) could prevent dysfunction from developing in the streptozotocin (STZ)-induced rat model of type 1 diabetes. Materials and methods: One week after induction of diabetes, STZ rats began a 4-week treatment protocol of twice-weekly i.v. injections of 2 μg VEGF or inactivated VEGF. Corresponding non-diabetic rats served as controls. Agonist-evoked vascular responses were recorded 1 day after the last treatment in anaesthetised rats. Results: Acetylcholine (0.1-12.5 μg/kg) evoked increases in superior mesenteric arterial conductance and decreases in mean blood pressure, while methoxamine (12.5-100 μg/kg) and endothelin-1 (100-1,200 pmol/kg) evoked decreases in superior mesenteric arterial conductance and increases in mean blood pressure. These responses to all three agonists were attenuated in STZ rats, and chronic treatment with VEGF improved these responses dramatically. Both the reduction in plasma nitrate and nitrite and the elevation in aortic superoxide associated with STZ diabetes were normalised with VEGF treatment. VEGF also prevented the apparent paradoxical increased endothelial nitric oxide synthase expression seen in untreated STZ rats. Conclusions/interpretation: Chronic treatment with VEGF early in diabetes is able to prevent the attenuated agonistevoked vascular responses in STZ rats and normalise the oxidative environment associated with the disease.

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Section: Discussionmentioning

confidence: 99%

“…In streptozotocin (STZ)-induced diabetic rats, this endothelial dysfunction is characterised by attenuated agonist-evoked responses to acetylcholine [3]. The impaired acetylcholine-evoked responses appear to be related, at least in part, to inactivation of nitric oxide (NO) by reactive oxygen species, notably the superoxide anion [4].…”

Section: Introductionmentioning

confidence: 99%

Chronic treatment with vascular endothelial growth factor preserves agonist-evoked vascular responses in the streptozotocin-induced diabetic rat

et al. 2006

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“…All other chemicals were obtained from Sigma. Solutions of authentic NO (ϳ1 mM) were prepared in helium-deoxygenated distilled water as described (28).…”

Section: Methodsmentioning

confidence: 99%

Ascorbic Acid Enhances Endothelial Nitric-oxide Synthase Activity by Increasing Intracellular Tetrahydrobiopterin

Huang¹,

Vita²,

Venema³

et al. 2000

Journal of Biological Chemistry

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337

186

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Ascorbic acid enhances NO bioactivity in patients with vascular disease through unclear mechanism(s).We investigated the role of intracellular ascorbic acid in endothelium-derived NO bioactivity. Incubation of porcine aortic endothelial cells (PAECs) with ascorbic acid produced time-and dose-dependent intracellular ascorbic acid accumulation that enhanced NO bioactivity by 70% measured as A23187-induced cGMP accumulation. This effect was due to enhanced NO production because ascorbate stimulated both PAEC nitrogen oxide (NO 2 ؊ ؉ NO 3 Ϫ ) production and L-arginine to L-citrulline conversion by 59 and 72%, respectively, without altering the cGMP response to authentic NO. Ascorbic acid also stimulated the catalytic activity of eNOS derived from either PAEC membrane fractions or baculovirus-infected Sf9 cells. Ascorbic acid enhanced bovine eNOS V max by ϳ50% without altering the K m for L-arginine. The effect of ascorbate was tetrahydrobiopterin (BH 4 )-dependent, because ascorbate was ineffective with BH 4 concentrations >10 M or in PAECs treated with sepiapterin to increase intracellular BH 4 . The effect of ascorbic acid was also specific because A23187-stimulated cGMP accumulation in PAECs was insensitive to intracellular glutathione manipulation and only ascorbic acid, not glutathione, increased the intracellular concentration of BH 4 . These data suggest that ascorbic acid enhances NO bioactivity in a BH 4 -dependent manner by increasing intracellular BH 4 content.Nitric oxide is produced from L-arginine in the vascular endothelium by the endothelial isoform of nitric-oxide synthase (NOS).1 Endothelial production of NO is crucial in the control of vascular tone (1), arterial pressure (2-4), smooth muscle cell proliferation (5, 6), and platelet adhesion to the endothelial surface (7). Impaired endothelium-derived NO bioactivity is a common feature of many vascular diseases (8 -10) that is thought to contribute to their clinical manifestations (11,12).The action of NO is particularly sensitive to the local availability of superoxide. Both endothelial elaboration of NO and arterial relaxation in response to nitrovasodilators are dependent upon intact copper-zinc superoxide dismutase (SOD) activity (13,14). Animal models of hypercholesterolemia (15, 16) and hypertension (17) demonstrate an excess vascular superoxide flux that is linked to reduced NO bioactivity. Conversely, increasing vascular SOD activity enhances NO-mediated arterial relaxation in experimental models of atherosclerosis (18,19) and hypertension (17). Thus, scavenging superoxide has important implications for NO bioactivity under both normal and pathologic conditions. Ascorbic acid also efficiently scavenges superoxide (20) and numerous studies in a host of pathologic conditions such as diabetes (21), hypercholesterolemia (22), smoking (23), and hypertension (24) indicate that NO bioactivity is improved by parenteral ascorbic acid at supraphysiologic concentrations (ϳ10 mM). We have observed enhanced NO bioactivity in atherosclerotic patients aft...

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“…64 An elevation in reactive oxygen species (ROS) represents an essential component of atherosclerotic plaque development that contributes to nonenzymatic formation of isoprostanes from arachidonic acid. [65][66][67][68] An important source of ROS are reduced nicotinamide adenine dinucleotide phosphate † PϽ0.005 n-LDL versus control; ‡ PϽ0.005 ox-LDL versus control. Probability values are for the significance of ox-LDL and n-LDL effects on NO levels (*PϽ0.005).…”

Section: Evidence For Cholesterol Crystalline Membrane Domains In Athmentioning

confidence: 99%

Effects of HMG-CoA Reductase Inhibitors on Endothelial Function

2004

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Abstract-Certain pleiotropic activities reported for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are related to reductions in cellular cholesterol biosynthesis and isoprenoid levels. In endothelial cells, these metabolic changes contribute to favorable effects on nitric oxide (NO) bioavailability. Given the essential role of NO in preserving vascular structure and function, this effect of statins is of considerable therapeutic importance. Statins have been demonstrated to restore endothelial NO production by several mechanisms, including upregulating endothelial NO synthase (eNOS) protein expression and blocking formation of reactive oxygen species. In this article, we will discuss additional ways in which statins restore endothelial NO production and improve endothelial function.(1) Statins modulate membrane microdomain formation, resulting in reduced expression of proteins that specifically inhibit eNOS activation. (2) Statins reduce sterol biosynthesis, thus interfering with the formation of pathologic microdomains, including cholesterol crystalline structures. This observation has important implications for plaque stabilization, as these microdomains contribute to cholesterol crystal formation and endothelial apoptosis. Finally, (3) statins improve endothelial function by interfering with oxidative stress pathways through both enzymatic and nonenzymatic mechanisms. The relationships between membrane microdomains, cholesterol biosynthesis, and endothelial function will be discussed.

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Vascular Superoxide Dismutase Deficiency Impairs Endothelial Vasodilator Function Through Direct Inactivation of Nitric Oxide and Increased Lipid Peroxidation

Cited by 136 publications

References 37 publications

Chronic treatment with vascular endothelial growth factor preserves agonist-evoked vascular responses in the streptozotocin-induced diabetic rat

Chronic treatment with vascular endothelial growth factor preserves agonist-evoked vascular responses in the streptozotocin-induced diabetic rat

Ascorbic Acid Enhances Endothelial Nitric-oxide Synthase Activity by Increasing Intracellular Tetrahydrobiopterin

Effects of HMG-CoA Reductase Inhibitors on Endothelial Function

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