Endothelial Nitric Oxide Synthase Uncoupling Impairs Endothelial Progenitor Cell Mobilization and Function in Diabetes

Thum, Thomas; Fraccarollo, Daniela; Schultheiß, Maximilian; Froese, S.; Galuppo, Paolo; Widder, Julian; Tsikas, Dimitrios; Ertl, Georg; Bauersachs, Johann

doi:10.2337/db06-0699

Cited by 361 publications

(276 citation statements)

References 53 publications

(87 reference statements)

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“…This is in line with previous observations [42,[45][46][47][48] and may also reflect one mechanism by which statin therapy improves vascular dysfunction in the setting of diabetes, especially when bearing in mind, that eNOS uncoupling seems to be an important source of superoxide in EPCs, too [42].…”

Section: By Which Mechanism Does Atorvastatin Prevent Enos Uncoupling?supporting

confidence: 80%

“…We also established a substantial decrease in the levels of circulating EPCs, all of which may have also contributed to vascular dysfunction in the setting of diabetes mellitus [41]. Interestingly, in a recent paper Thum and coworkers showed eNOS uncoupling in EPCs as a feature of EPC malfunction in diabetes [42].…”

Section: Vascular Dysfunction Oxidative Stress and Diabetes Mellitusmentioning

confidence: 99%

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Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus

et al. 2008

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Objective-HMG-CoA reductase inhibitors have been shown to upregulate GTP cyclohydrolase I (GTPCH-I), the key enzyme for tetrahydrobiopterin de novo synthesis and to normalize tetrahydrobiopterin levels in hyperglycemic endothelial cells. We sought to determine whether in vivo treatment with the HMG-CoA reductase inhibitor atorvastatin is able to upregulate the GTPCH-I, to recouple eNOS and to normalize endothelial dysfunction in an experimental model of diabetes mellitus.Methods and results-In male Wistar rats, diabetes was induced by streptozotocin (STZ, 60 mg/ kg). In STZ rats, atorvastatin feeding (20 mg/kg/d, 7 weeks), normalized vascular dysfunction as analyzed by isometric tension studies, levels of circulating endothelial progenitor cells (FACSanalysis), superoxide formation (assessed by lucigenin-enhanced chemiluminescence and dihydroethidium staining), vascular levels of the phosphorylated vasodilator-stimulated phosphoprotein (P-VASP), tyrosine nitration of the prostacyclin synthase, expression of GTPCH-I, dihydrofolate reductase and eNOS, translocation of regulatory NADPH oxidase subunits rac1, p47phox and p67phox (assessed by Western blot) and vascular tetrahydrobiopterin levels as measured by HPLC. Dihydroethidine staining revealed that the reduction of vascular superoxide was at least in part due to eNOS recoupling.Conclusion-HMG-CoA reductase inhibition normalizes endothelial function and reduces oxidative stress in diabetes by inhibiting activation of the vascular NADPH oxidase and by preventing

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Section: By Which Mechanism Does Atorvastatin Prevent Enos Uncoupling?supporting

confidence: 80%

Section: Vascular Dysfunction Oxidative Stress and Diabetes Mellitusmentioning

confidence: 99%

Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus

et al. 2008

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“…Treatment of diabetic EPC with BH4 led to a coupling of former uncoupled eNOS, normalized intracellular ROS levels, and improved EPC function (105). Accordingly, EPCs from diabetic patients generate more ROS, at least in part due to eNOS uncoupling and increased NADPH oxidase activity, leading to a reduction in NO bioavailability (88,105). Treatment of glucose-stressed EPCs with superoxide dismutase in vitro attenuated superoxide anion (O 2 -) generation, restored NO production, and partially normalized their ability to form colonies (35).…”

Section: Diabetesmentioning

confidence: 99%

“…However, the exact mechanism of the contribution of early EPCs to upkeep vascular integrity remains uncertain. Early EPCs secrete various pro-angiogenic factors, such as VEGF, stromal SDF-1, and NO (105,117), thus contributing to angiogenesis and vascular repair by paracrine mechanisms (Fig. 2).…”

Section: Endothelial Colony Forming Unitsmentioning

confidence: 99%

Critical Role of the Nitric Oxide/Reactive Oxygen Species Balance in Endothelial Progenitor Dysfunction

Fleißner

Thum²

2011

Antioxidants & Redox Signaling

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Endothelial injury and dysfunction are critical events in the pathogenesis of cardiovascular disease. During these processes, an impaired balance of nitric oxide bioavailability and oxidative stress is mechanistically involved. Circulating angiogenic cells (including early and late outgrowth endothelial progenitor cells (EPC)) contribute to formation of new blood vessels, neovascularization, and homeostasis of the vasculature, and are highly sensitive for misbalance between NO and oxidative stress. We here review the role of the endothelial nitric oxide synthase and oxidative stress producing enzyme systems in EPC during cardiovascular disease. We also focus on the underlying molecular mechanisms and potential emerging drug-and gene-based therapeutic strategies to improve EPC function in cardiovascular diseased patients. Antioxid. Redox Signal. 15, 933-948.

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“…PKA activation (55). In addition to ameliorating endothelial dysfunction in diabetics, statins and thiazolidinediones are effective in improving circulating proangiogenic cell function and number (56)(57)(58). NO donor drugs have been developed, as for example S-nitrosothiols that have been effectively studied in trials using coated stent and other devices to prevent neointima formation (59).…”

Section: Enos/no-based Therapies For Vascular Diseasesmentioning

confidence: 99%

The genetics of exceptional longevity identifies new druggable targets for vascular protection and repair

Puca

Spinetti

Vono

et al. 2016

Pharmacological Research

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms AbstractTherapeutic angiogenesis is a relatively new medical strategy in the field of cardiovascular diseases.The underpinning concept is that angiogenic growth factors or proangiogenic cells could be exploited therapeutically in cardiovascular patients to enhance native revascularization responses to an ischemic insult, thereby accelerating tissue healing. The initial enthusiasm generated by preclinical studies has been tempered by the modest success of clinical trials assessing therapeutic angiogenesis. Similarly, proangiogenic cell therapy has so far not maintained the original promises.Intriguingly, the current trend is to consider regeneration as a prerogative of the youngest organism.Consequentially, the embryonic and foetal models are attracting much attention for clinical translation into corrective modalities in the adulthood. Scientists seem to undervalue the lesson from Mother Nature, e.g. all humans are born young but very few achieve the goal of an exceptional healthy longevity. Either natural experimentation is driven by a supreme intelligence or stochastic phenomena, one has to accept the evidence that healthy longevity is the fruit of an evolutionary process lasting million years. It is therefore extremely likely that results of this natural experimentation are more reliable and translatable than the intensive, but very short human investigation on mechanisms governing repair and regeneration. With this preamble in mind, here we propose to shift the focus from the very beginning to the very end of human life and thus capture the secret of prolonged health span to improve well-being in the adulthood.

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Endothelial Nitric Oxide Synthase Uncoupling Impairs Endothelial Progenitor Cell Mobilization and Function in Diabetes

Cited by 361 publications

References 53 publications

Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus

Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus

Critical Role of the Nitric Oxide/Reactive Oxygen Species Balance in Endothelial Progenitor Dysfunction

The genetics of exceptional longevity identifies new druggable targets for vascular protection and repair

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