Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation

Dimmeler, Stefanie; Fleming, Ingrid; Fißlthaler, Beate; Hermann, Corinna; Busse, Rudi; Zeiher, Andreas M.

doi:10.1038/21224

Cited by 3,280 publications

(2,907 citation statements)

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“…eNOS is an important enzyme in the regulation of BP, vascular tone, and angiogenesis. Several protein kinases including AMPK activate eNOS by phosphorylating Ser1177 in response to various stimuli (Dimmeler et al., 1999; Fulton et al., 1999). Therefore, the mechanism of the antihypertensive effect of compound H may include activation of the SIRT1‐AMPK‐eNOS pathway, inhibition of MMP and TGFβ, and attenuation of arterial remodeling and stiffening.…”

Section: Discussionmentioning

confidence: 99%

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Chen

Sun

2018

Aging Cell

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Summary DNA methylation increases with age. The objective of this study was to investigate whether compound H, a potential activator of DNA demethylases, attenuates aging‐related arterial stiffness and hypertension. Aged mice (24–27 months) and adult mice (12 months) were used. Pulse wave velocity (PWV), a direct measure of arterial stiffness, and blood pressure (BP) were increased significantly in aged mice. Notably, daily treatments with compound H (15 mg/kg, IP) for 2 weeks significantly attenuated the aging‐related increases in PWV and BP. Compound H abolished aging‐associated downregulation of secreted Klotho (SKL) levels in both kidneys and serum likely by enhancing DNA demethylase activity and decreasing DNA methylation. Aging‐related arterial stiffness was associated with accumulation of stiffer collagen and degradation of compliant elastin which are accompanied by increased expression of MMP2, MMP9, TGF‐β1, and TGF‐β3. These changes were effectively attenuated by compound H, suggesting rejuvenation of aged arteries. Compound H also rescued downregulation of Sirt1 deacetylase, AMPKα, and eNOS activities in aortas of aged mice. In cultured smooth muscle cells (SMCc) Klotho‐deficient serum upregulated expression of MMPs and TGFβ which, however, was not affected by compound H. In conclusion, compound H attenuates aging‐associated arterial stiffness and hypertension by activation of DNA demethylase which increases renal SKL expression and consequently circulating SKL levels leading to activation of the Sirt1‐AMPK‐eNOS pathway in aortas of aged mice.

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Section: Discussionmentioning

confidence: 99%

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Chen

Sun

2018

Aging Cell

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“…An increase in shear stress (eg, during physical activity) has been proved to enhance eNOS mRNA and protein expression and promote phosphorylation of the serine 1177 residue of the enzyme, thereby boosting vascular NO production 31, 32, 33, 34. However, animal studies suggest that after a few months of exercise training, eNOS expression levels reduce to the preexercise state 35.…”

Section: Adaptation Of Coronary Circulation To Exercise Training In Tmentioning

confidence: 99%

Physical Activity in the Prevention and Treatment of Coronary Artery Disease

Winzer

Woitek

Linke

2018

JAHA

172

120

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“…The induction of endothelial NOS (eNOS, NOS-3) by estrogen, fibroblast growth factor or epidermal growth factor in endothelial cells involves the Ras-ERK pathway [38,233]. eNOS is phosphorylated, and thus activated, by the serine/threonine protein kinase AKT, which is recruited to the cell membrane by PI3-kinase as an antiapoptotic mechanism in the response of endothelial cells to shear stress [54]. In the case of neuronal NOS (nNOS, NOS-1), the induction of mRNA, protein expression and activity by nerve growth factor (NGF) in PC12 cells involves activation of the Ras-ERK1/2 pathway, initiating a kinase cascade proceeding from Raf via MEK to ERK [177].…”

Section: Nitric Oxide and Mapk Signalingmentioning

confidence: 99%

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

Schroeter

Boyd

Spencer

et al. 2002

Neurobiology of Aging

308

178

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Oxidative and nitrosative stress is increasingly associated with the pathology of neurodegeneration and aging. The molecular mechanisms underlying oxidative/nitrosative stress-induced neuronal damage are emerging and appear to involve a mode of death in which mitogen-activated protein kinase (MAPK) signaling pathways are strongly implicated. Thus, attention is turning towards the modulation of intracellular signaling as a therapeutic approach against neurodegeneration. Both endogenous and dietary agents have been suggested as potent modulators of intracellular signal transduction, e.g. nitric oxide and flavonoids, respectively. This review addresses recent findings on the biological effects of flavonoids and nitric oxide in neurodegeneration and aims to elucidate the rationale for their prospective use as modulators of cellular signal transduction. © 2002 Elsevier Science Inc. All rights reserved.Keywords: Apoptosis; Oxidative stress; Neuron; Flavonoids; MAP kinase; JNK; ERK; Epicatechin; Nitric oxide; Mitochondria; Redox status; Polyphenols Abbreviations: AKT, serine/threonine kinase (also known as protein kinase B); AP-1, activator protein-1; Apaf-1, apoptosis protease activating factor-1; ASK1, apoptosis signal-regulating kinase-1; Bad, Bcl-2/BclX Lassociated death promoting protein; Bax, pro-apoptotic protein of the Bcl-2 family; Bcl-2, B-cell lymphoma 2: protein with anti-apoptotic properties; BclX L , long form of Bclx: anti-apoptotic protein of the Bcl-2 family; Caspase, cysteinyl aspartic acid-protease; c-Jun, mammalian equivalent of Jun: part of the AP-1 transcription complex; CREB, cAMP response element binding protein; DIABLO/smac, mitochondria-related pro-apoptotic protein: inhibits XIAP; ERK1/2, extracellular signal-related kinase; Fas, CD95: member of the TNF receptor family; GSHST, glutathione Stransferase; JNK, c-Jun amino-terminal kinase; MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase; MAPKKK, MAPKK kinase; MEK1/2, ERK1/2-specific MAPKK; MKK4/7, JNK-specific MAPKK; MSK1, mitogen-and stress-activated kinase-1; NF-B, nuclear factor of immunoglobulin k locus in B-cells; ONOO − , peroxynitrite anion; p53, pro-apoptotic tumor suppressor gene product; PI3-kinase, phosphoinositol 3-kinase; Ras, small G-protein; RNS, reactive nitrogen species; ROS, reactive oxygen species; RSK, pp90 ribosomal S6 kinase; SAPK, stressactivated protein kinase; XIAP, X-linked inhibitor of apoptosis: inhibits the activation of caspase-9

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Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation

Cited by 3,280 publications

References 29 publications

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Physical Activity in the Prevention and Treatment of Coronary Artery Disease

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

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