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  • 1
    Online Resource
    Online Resource
    Inhibition of Vascular c‐Jun N‐Terminal Kinase 2 Improves Obesity‐Induced Endothelial Dysfunction After Roux‐en‐Y Gastric Bypass
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Journal of the American Heart Association Vol. 6, No. 11 ( 2017-11)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 6, No. 11 ( 2017-11)
    Abstract: Roux‐en‐Y gastric bypass ( RYGB ) reduces obesity‐associated comorbidities and cardiovascular mortality. RYGB improves endothelial dysfunction, reducing c‐Jun N‐terminal kinase ( JNK ) vascular phosphorylation. JNK activation links obesity with insulin resistance and endothelial dysfunction. Herein, we examined whether JNK 1 or JNK 2 mediates obesity‐induced endothelial dysfunction and if pharmacological JNK inhibition can mimic RYGB vascular benefits. Methods and Results After 7 weeks of a high‐fat high‐cholesterol diet, obese rats underwent RYGB or sham surgery; sham–operated ad libitum–fed rats received, for 8 days, either the control peptide D‐ TAT or the JNK peptide inhibitor D‐ JNK i‐1 (20 mg/kg per day subcutaneous). JNK peptide inhibitor D‐ JNK i‐1 treatment improved endothelial vasorelaxation in response to insulin and glucagon‐like peptide‐1, as observed after RYGB . Obesity increased aortic phosphorylation of JNK 2, but not of JNK 1. RYGB and JNK peptide inhibitor D‐ JNK i‐1 treatment blunted aortic JNK 2 phosphorylation via activation of glucagon‐like peptide‐1–mediated signaling. The inhibitory phosphorylation of insulin receptor substrate‐1 was reduced, whereas the protein kinase B/endothelial NO synthase pathway was increased and oxidative stress was decreased, resulting in improved vascular NO bioavailability. Conclusions Decreased aortic JNK 2 phosphorylation after RYGB rapidly improves obesity‐induced endothelial dysfunction. Pharmacological JNK inhibition mimics the endothelial protective effects of RYGB . These findings highlight the therapeutic potential of novel strategies targeting vascular JNK 2 against the severe cardiovascular disease associated with obesity.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.117.006441
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 2653953-6
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  • 2
    Online Resource
    Online Resource
    Omega‐3 Fatty Acids and Heart Rhythm, Rate, and Variability in Atrial Fibrillation
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Journal of the American Heart Association Vol. 12, No. 11 ( 2023-06-06)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 12, No. 11 ( 2023-06-06)
    Abstract: Previous randomized control trials showed mixed results concerning the effect of omega‐3 fatty acids (n‐3 FAs) on atrial fibrillation (AF). The associations of n‐3 FA blood levels with heart rhythm in patients with established AF are unknown. The goal of this study was to assess the associations of total and individual n‐3 FA blood levels with AF type (paroxysmal versus nonparoxysmal), heart rate (HR), and HR variability in patients with AF. Methods and Results Total n‐3 FAs, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, and alpha‐linolenic acid blood levels were determined in 1969 patients with known AF from the SWISS‐AF (Swiss Atrial Fibrillation cohort). Individual and total n‐3 FAs were correlated with type of AF, HR, and HR variability using standard logistic and linear regression, adjusted for potential confounders. Only a mild association with nonparoxysmal AF was found with total n‐3 FA (odds ratio [OR], 0.97 [95% CI, 0.89–1.05] ) and docosahexaenoic acid (OR, 0.93 [95% CI, 0.82–1.06]), whereas other individual n‐3 FAs showed no association with nonparoxysmal AF. Higher total n‐3 FAs (estimate 0.99 [95% CI, 0.98–1.00] ) and higher docosahexaenoic acid (0.99 [95% CI, 0.97–1.00]) tended to be associated with slower HR in multivariate analysis. Docosapentaenoic acid was associated with a lower HR variability triangular index (0.94 [95% CI, 0.89–0.99] ). Conclusions We found no strong evidence for an association of n‐3 FA blood levels with AF type, but higher total n‐3 FA levels and docosahexaenoic acid might correlate with lower HR, and docosapentaenoic acid with a lower HR variability triangular index.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.122.027646
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
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  • 3
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    Online Resource
    Whole blood omega-3 fatty acid concentrations are inversely associated with blood pressure in young, healthy adults
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Journal of Hypertension Vol. 36, No. 7 ( 2018-07), p. 1548-1554
    Details
    In: Journal of Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. 7 ( 2018-07), p. 1548-1554
    Type of Medium: Online Resource
    ISSN: 0263-6352
    URL: Article
    DOI: 10.1097/HJH.0000000000001728
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 2017684-3
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  • 4
    Online Resource
    Online Resource
    Aging Induces Endothelial Dysfunction While Sparing Arterial Thrombosis
    Ovid Technologies (Wolters Kluwer Health) ; 2010
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 30, No. 10 ( 2010-10), p. 1960-1967
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 30, No. 10 ( 2010-10), p. 1960-1967
    Abstract: Objective— To assess the effects of aging on arterial thrombus formation by comparing 2-year-old with 11-week-old C57Bl6 mice. Methods and Results— Aging is a major risk factor for cardiovascular disease. In humans, assessing the direct effects of aging on vascular homeostasis is difficult because it occurs in the presence of other risk factors. Arterial thrombosis is the critical event in cardiovascular diseases; however, it is not known whether aging per se promotes its occurrence. Mice represent an interesting system to address this issue because they age without spontaneously developing other risk factors. Organ chamber experiments confirmed the advanced level of aging of old mice. As previously shown, old mice exhibited endothelial dysfunction; however, arterial thrombosis induced by photochemical injury was unchanged. Arterial tissue factor expression and activity; expressions of tissue factor pathway inhibitor, thrombomodulin, and plasminogen activator inhibitor 1; prothrombin time; partial thromboplastin time; thrombin-antithrombin complex; and platelet activation were comparable in both groups. Conclusion— Although these results cannot be directly extrapolated to humans, this study contributes novel important information on the direct effect of aging on arterial thrombosis and underscores the importance of controlling modifiable risk factors in aged individuals.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.110.206920
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2010
    detail.hit.zdb_id: 1494427-3
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  • 5
    Online Resource
    Online Resource
    Final Common Molecular Pathways of Aging and Cardiovascular Disease : Role of the p66 Shc Protein
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 28, No. 4 ( 2008-04), p. 622-628
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 28, No. 4 ( 2008-04), p. 622-628
    Abstract: Mice carrying a targeted mutation of the p66 Shc gene display reduced production of intracellular oxidants, increased resistance to oxidative stress-induced apoptosis, prolonged lifespan, and are protected against vascular, cardiac, and renal impairment attributable to hypercholesterolemia, aging, diabetes, and ischemia/reperfusion. The present review focuses on the biochemical function of the p66 Shc adaptor protein as well as on the mechanisms linking p66 Shc to the pathophysiology of aging and cardiovascular disease.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.107.156059
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2008
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  • 6
    Online Resource
    Online Resource
    Oxidized Low-Density Lipoprotein Activates p66 Shc via Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1, Protein Kinase C-β, and c-Jun N-Terminal Kinase Kinase in Human Endothelial Cells
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 31, No. 9 ( 2011-09), p. 2090-2097
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 31, No. 9 ( 2011-09), p. 2090-2097
    Abstract: Deletion of the mitochondrial gene p66 Shc protects from endothelial dysfunction and atherosclerotic plaque formation in mice fed a high-fat diet. However, the molecular mechanisms underlying this beneficial effect have not yet been delineated. The present study was designed to elucidate the proatherogenic mechanisms by which p66 Shc mediates oxidized low-density lipoprotein (oxLDL) uptake by the endothelium, a critical step in plaque formation. Methods and Results— Incubation of human aortic endothelial cells with oxLDL led to phosphorylation of p66 Shc at Ser36. Inhibition of lectin-like oxLDL receptor-1 prevented p66 Shc phosphorylation, confirming that this effect is mediated by lectin-like oxLDL receptor-1. OxLDL also increased phosphorylation of protein kinase C β 2 (PKCβ 2 ) at both Thr641 and Ser660, as well as c-Jun N-terminal kinase (JNK). Furthermore, inhibition of PKCβ 2 prevented the activation of JNK, suggesting that PKCβ2 is upstream of JNK. Finally, p66 Shc silencing blunted oxLDL-induced O 2 −. production, underscoring the critical role of p66 Shc in oxLDL-induced oxidative stress in endothelial cells. Conclusion— In this study we provide the molecular mechanisms mediating the previously observed atherogenic properties of p66 Shc . Taken together, our data set the stage for the design of novel therapeutic tools to retard atherogenesis through the inhibition of p66 Shc .
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.111.229260
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
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  • 7
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    Online Resource
    Abstract 167: Genetic Deletion of p66Shc Adaptor Protein Leads to Increased Myocardial Infarction by Inhibiting RISK and SAFE Prosurvival Pathways
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Circulation Research Vol. 113, No. suppl_1 ( 2013-08)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 113, No. suppl_1 ( 2013-08)
    Abstract: Background— Formation of reactive oxygen species (ROS) contributes to many pathophysiological processes. Although ROS production is also involved in some physiological processes, the imbalance between their generation and removal, i.e. oxidative stress, plays a major role in particular in myocardial injury caused by ischemia-reperfusion (I/R). The mammalian Shc locus encodes three Shc isoforms: p46 Shc , p52 Shc and p66 Shc . The p66 Shc is not involved in mitogenic signals as p46 Shc /p52 Shc , but it functions as a critical mediator of intracellular oxidative signal transduction. Various studies relate p66 Shc to cardiovascular disease; however, few data are available on the role of p66 Shc in myocardial I/R. Methods and Results— 8-12-week-old male p66 Shc deficient ( p66 Shc-/- ) mice and corresponding C57Bl/6 wild-type (WT) control mice were subjected in vivo to different durations of ischemia (30, 45 and 60 min) followed by 24h of reperfusion. Infarct size was assessed morphologically and by MRI. After 30 min of ischemia, p66 Shc-/- mice developed markedly larger infarcts as compared to WT. This effect was confirmed by in vivo silencing of p66 Shc prior to I/R. Both genetic deletion and silencing of p66 Shc displayed increased post-ischemic levels of serum cardiac troponin I (cTnI). However, the observed effect on infarct size was limited to 30 min of ischemia since by increasing ischemia duration to either 45 or 60 min infarct size did no longer differ between p66 Shc-/- and WT mice. Moreover, differently from WT, infarct size in p66 Shc-/- was not significantly larger with increasing duration of ischemia (from 30 to 60 min). On the molecular level the observed effect was linked to the inhibition of activation by phosphorylation of protein kinase Akt and transcription factor STAT3 - two key members of prosurvival pathways RISK and SAFE, respectively. Conclusions— Our data suggest that genetic deletion of p66 Shc leads to an increased sensitivity to myocardial infarction with larger infarcts with shorter, but not prolonged ischemia, and that RISK and SAFE prosurvival pathways are involved. Therefore, activation of p66 Shc may provide resistance to ischemia and represent a novel therapeutic target in the early phase of myocardial infarction.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.113.suppl_1.A167
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 1467838-X
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  • 8
    Online Resource
    Online Resource
    Adaptor Protein p66 Shc Mediates Hypertension-Associated, Cyclic Stretch–Dependent, Endothelial Damage
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Hypertension Vol. 64, No. 2 ( 2014-08), p. 347-353
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 64, No. 2 ( 2014-08), p. 347-353
    Abstract: Increased cyclic stretch to the vessel wall, as observed in hypertension, leads to endothelial dysfunction through increased free radical production and reduced nitric oxide bioavailability. Genetic deletion of the adaptor protein p66 Shc protects mice against age-related and hyperglycemia-induced endothelial dysfunction, as well as atherosclerosis and stroke. Furthermore, p66 Shc mediates vascular dysfunction in hypertensive mice. However, the direct role of p66 Shc in mediating mechanical force–induced free radical production is unknown; thus, we studied the effect of cyclic stretch on p66 Shc activation in primary human aortic endothelial cells and aortic endothelial cells isolated from normotensive and hypertensive rats. Exposure of human aortic endothelial cells to cyclic stretch led to a stretch- and time-dependent p66 Shc phosphorylation at Ser36 downstream of integrin α5β1 and c-Jun N-terminal kinase. In parallel, nicotinamide adenine dinucleotide phosphate oxidase activation, as well as production of reactive oxygen species, increased, whereas nitric oxide bioavailability decreased. Silencing of p66 Shc blunted stretch-increased superoxide anion production and nicotinamide adenine dinucleotide phosphate oxidase activation and restored nitric oxide bioavailability. In line with the above, activation of p66 Shc increased in isolated aortic endothelial cells of spontaneously hypertensive rats compared with normotensive ones. Pathological stretch by activating integrin α5β1 and c-Jun N-terminal kinase phosphorylates p66 Shc at Ser36, augments reactive oxygen species production via nicotinamide adenine dinucleotide phosphate oxidase, and in turn reduces nitric oxide bioavailability. This novel molecular pathway may be relevant for endothelial dysfunction and vascular disease in hypertension.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.113.02129
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 2094210-2
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  • 9
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    Online Resource
    Abstract 3741: Stress Promotes Arterial Thrombosis through Activation of the Sympathetic Nervous System
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Circulation Vol. 118, No. suppl_18 ( 2008-10-28)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 118, No. suppl_18 ( 2008-10-28)
    Abstract: Background: Several lines of evidence demonstrate a correlation between stress and cardiovascular mortality and morbidity. Myocardial infarction can be triggered by life threatening events such as earthquakes or missile attacks, and even every day stressful situations such as anger were shown to correlate with adverse cardiovascular events, primarily caused by arterial thrombus formation. The sympathetic nervous system is known to mediate various stress-related effects; however, a mechanism linking stress and thrombosis has not been described. Methods: To investigate the influence of acute stress on arterial thrombosis, mice were subjected to a restraint stress protocol for 20 hours. Subsequently, arterial thrombosis was induced by photochemical injury in vivo . Furthermore, coagulation times (PT, aPTT) and tissue factor activity were assayed in plasma and carotid artery, respectively. In addition, tail bleeding time was assessed. To investigate the role of the sympathetic nervous system, chemical sympathectomy was performed by treating mice with 6-Hydroxydopamine (OHDA) or control vehicle, respectively. Results: Time to thrombotic occlusion was significantly decreased in stressed mice as compared to controls (−26.7 ± 4.0 minutes, p 〈 0.001, n=5). In sympathectomized mice stress failed to decrease time to occlusion (−8.1 ± 5.6 minutes, n.s., n=5); Sympathectomy alone had no effect on time to occlusion as compared to vehicle treatment. Tissue factor activity, tail bleeding time, and coagulation times remained unchanged under all conditions, indicating an unaltered state of vessel wall tissue factor, systemic coagulation and platelet function, respectively. Conclusions: Stress enhances arterial thrombosis via the sympathetic nervous system. The link between increased sympathetic activity and thrombus formation is still under investigation. These findings may open novel perspectives for the understanding of stress-induced cardiovascular events.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.118.suppl_18.S_478-c
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2008
    detail.hit.zdb_id: 1466401-X
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  • 10
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    Online Resource
    c-Jun N-Terminal Kinase 2 Deficiency Protects Against Hypercholesterolemia-Induced Endothelial Dysfunction and Oxidative Stress
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Circulation Vol. 118, No. 20 ( 2008-11-11), p. 2073-2080
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 118, No. 20 ( 2008-11-11), p. 2073-2080
    Abstract: Background— Hypercholesterolemia-induced endothelial dysfunction due to excessive production of reactive oxygen species is a major trigger of atherogenesis. The c-Jun-N-terminal kinases (JNKs) are activated by oxidative stress and play a key role in atherogenesis and inflammation. We investigated whether JNK2 deletion protects from hypercholesterolemia-induced endothelial dysfunction and oxidative stress. Methods and Results— Male JNK2 knockout ( JNK2 −/− ) and wild-type (WT) mice (8 weeks old) were fed either a high-cholesterol diet (HCD; 1.25% total cholesterol) or a normal diet for 14 weeks. Aortic lysates of WT mice fed a HCD showed an increase in JNK phosphorylation compared with WT mice fed a normal diet ( P 〈 0.05). Endothelium-dependent relaxations to acetylcholine were impaired in WT HCD mice ( P 〈 0.05 versus WT normal diet). In contrast, JNK2 −/− HCD mice did not exhibit endothelial dysfunction (96±5% maximal relaxation in response to acetylcholine; P 〈 0.05 versus WT HCD). Endothelium-independent relaxations were identical in all groups. A hypercholesterolemia-induced decrease in nitric oxide (NO) release of endothelial cells was found in WT but not in JNK2 −/− mice. In parallel, endothelial NO synthase expression was upregulated only in JNK2 −/− HCD animals, whereas the expression of antioxidant defense systems such as extracellular superoxide dismutase and manganese superoxide dismutase was decreased in WT but not in JNK2 −/− HCD mice. In contrast to JNK2 −/− mice, WT HCD displayed an increase in O 2 − and ONOO − concentrations as well as nitrotyrosine staining and peroxidation. Conclusions— JNK2 plays a critical role as a mediator of hypercholesterolemia-induced endothelial dysfunction and oxidative stress. Thus, JNK2 may provide a novel target for prevention of vascular disease and atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.108.765032
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2008
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