Ceramide-Induced Impairment of Endothelial Function Is Prevented by CuZn Superoxide Dismutase Overexpression

Didion, Sean P.; Faraci, Frank M.

doi:10.1161/01.atv.0000149868.74075.5d

Cited by 32 publications

(29 citation statements)

References 53 publications

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“…We have shown previously that the same concentration of PEG-SOD (100 U/ml) does not affect ACh-induced vasodilatation in control mice (4). Such findings suggest that under normal conditions, superoxide does not impair responses to endothelium-dependent agonists, consistent with findings in other blood vessels in mice and with other superoxide scavengers (6,7,12). Our results suggest that endothelium-dependent responses are impaired in the carotid artery and in cerebral arterioles in TallyHo mice and begin to implicate an important role for superoxide in this impairment.…”

Section: Discussionsupporting

confidence: 91%

“…Increases in superoxide are associated with endothelial dysfunction in many diseases, including atherosclerosis, hypertension, and Type I diabetes (2,6,8,9,30). However, very few studies have examined responses in the cerebral circulation in Type II diabetes (4,36,50) and even fewer have examined potential mechanisms of vascular dysfunction in Type II diabetes (4,27).…”

Section: Discussionmentioning

confidence: 99%

“…Function of carotid arteries was examined as previously described (6,9,49). After a 45-min equilibration period, vessels were precontracted submaximally (50 -60% of maximum) with the thromboxane analog 9,11-dideoxy-11␣,9␣-epoxymethanoprostaglandin F 2␣ (U-46619).…”

Section: Methodsmentioning

confidence: 99%

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Cerebral vascular dysfunction in TallyHo mice: a new model of Type II diabetes

Didion¹,

Lynch²,

Faraci³

2007

American Journal of Physiology-Heart and Circulatory Physiology

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.-The purpose of this study was to characterize vascular responses and to examine mechanisms of vascular dysfunction in TallyHo mice, a new polygenic model of Type II diabetes. Responses of cerebral arterioles and carotid arteries were examined in vivo by using a cranial window and in vitro by using tissue baths, respectively. Dilatation of cerebral arterioles (baseline diameter ϭ 33 Ϯ 1 m) in response to acetylcholine, but not to nitroprusside, was markedly reduced (P Ͻ 0.05) in TallyHo mice. Responses of cerebral arterioles to acetylcholine in TallyHo mice were restored to normal with polyethylene glycol-superoxide dismutase (100 U/ml; a superoxide scavenger). Responses to acetylcholine were also greatly impaired (P Ͻ 0.05) in the carotid arteries from TallyHo mice. Phenylephrine-and serotonin-, but not to KCl-or U46619-, induced contraction was increased two-to fourfold (P Ͻ 0.05) in carotid arteries of TallyHo mice. Responses to phenylephrine and serotonin were reduced to similar levels in the presence of Y-27632 (an inhibitor of Rho kinase; 3 mol/l). These findings provide the first evidence that vascular dysfunction is present in TallyHo mice and that oxidative stress and enhanced activity of Rho kinase may contribute to altered vascular function in this genetic model of Type II diabetes. carotid artery; cerebral circulation; endothelium; microcirculation EPIDEMIOLOGICAL STUDIES suggest that there is a marked increase in the number of vascular complications in patients with diabetes (21,22,51). For example, results from the Framingham study have found a two-to fourfold increased risk associated with diabetes and the development of other cardiovascular risk factors, including atherosclerosis, carotid artery disease, and stroke (21). Although Type II diabetes accounts for the majority (ϳ90%) of diabetes in humans (3), relatively little is known regarding vascular responses and mechanisms that produce vascular dysfunction in Type II diabetes compared with Type I diabetes.Whereas studies using ob/ob (leptin-deficient) and db/db (leptin receptor-deficient mice) have provided much insight into vascular alterations in the genetic models of Type II diabetes (8,19,25,42,(43)(44)(45)(46), such monogenic deficiencies in leptin and the leptin receptor are rare and are not always associated with the development of diabetes in humans (14). TallyHo mice represent a newly defined polygenetic model of Type II diabetes and are characterized by hyperglycemia, hyperinsulinemia, hyperlipidemia, and moderate obesity (23,

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cerebral vascular dysfunction in TallyHo mice: a new model of Type II diabetes

Didion¹,

Lynch²,

Faraci³

2007

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

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“…Relaxation of carotid arteries in response to acetylcholine and nitroprusside was measured after submaximal precontraction (50% to 60%) using the thromboxane analog, U46619 (9,11-dideoxy-11a,9a-epoxymethanoprostoglandin-F 2␣ ) as described previously. 8,9,18,19 To confirm that the effect of Ang II on endothelial function is mediated by superoxide, some responses were examined in the absence and presence of Tempol (a superoxide scavenger; 1 mmol/L). We have shown previously that this concentration of Tempol is very efficacious in improving endothelium-dependent responses.…”

Section: Chronic Ang II Infusion Blood Pressure Analysis and Vasculmentioning

confidence: 99%

IL-6 Deficiency Protects Against Angiotensin II–Induced Endothelial Dysfunction and Hypertrophy

Schrader

Kinzenbaw

Johnson

et al. 2007

ATVB

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Objective-The goal of this study was to test the hypothesis that IL-6 mediates the increases in superoxide, vascular hypertrophy, and endothelial dysfunction in response to angiotensin II (Ang II). Methods and Results-Responses of carotid arteries from control and IL-6 -deficient mice were examined after acute (22-hour) incubation with Ang II (10 nmol/L) or chronic infusion of Ang II (1.4 mg/kg/d for 14 days). The hypertrophic response and endothelial dysfunction produced by Ang II infusion was markedly less in carotid arteries from IL-6 -deficient mice than that in control mice. IL-6 deficiency also protected against endothelial dysfunction in response to acute (local) Ang II treatment (eg, 100 mol/L acetylcholine produced 100Ϯ4 and 98Ϯ4% relaxation in vehicle-treated and 51Ϯ4 and 99Ϯ4% relaxation in Ang II-treated, control, and IL-6 -deficient vessels, respectively). Endothelial dysfunction could be reproduced in vessels from IL-6 -deficient mice with combined Ang II plus IL-6 (0.1 nmol/L) treatment. Increases in vascular superoxide and IL-6, as well as reductions in endothelial nitric oxide synthase mRNA expression, produced by Ang II were absent in IL-6 -deficient mice. Conclusions-These data demonstrate that IL-6 is essential for Ang II-induced increases in superoxide, endothelial dysfunction, and vascular hypertrophy. (Arterioscler Thromb Vasc Biol.

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“…In addition to apoptosis, ceramides have been involved in endothelial oxidative stress (38,48,49), growth arrest (50, 51), cytoskeletal changes (52), and senescence (53). Through these effects, ceramides regulate major aspects of lung endothelial cell function and, not surprisingly, have been involved in the pathogenesis of several conditions associated with pulmonary vascular dysfunction.…”

Section: Significance Of Ceramide-mediated Pulmonary Vascular Responsmentioning

confidence: 99%