Journal ArticleDOI
Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation
Stefanie Dimmeler,Ingrid Fleming,Beate Fisslthaler,Corinna Hermann,Rudi Busse,Andreas M. Zeiher +5 more
TLDR
It is demonstrated that the serine/threonine protein kinase Akt/PKB mediates the activation of eNOS, leading to increased NO production, and represents a novel Ca2+-independent regulatory mechanism for activation ofeNOS.Abstract:
Nitric oxide (NO) produced by the endothelial NO synthase (eNOS) is a fundamental determinant of cardiovascular homesotasis: it regulates systemic blood pressure, vascular remodelling and angiogenesis. Physiologically, the most important stimulus for the continuous formation of NO is the viscous drag (shear stress) generated by the streaming blood on the endothelial layer. Although shear-stress-mediated phosphorylation of eNOS is thought to regulate enzyme activity, the mechanism of activation of eNOS is not yet known. Here we demonstrate that the serine/threonine protein kinase Akt/PKB mediates the activation of eNOS, leading to increased NO production. Inhibition of the phosphatidylinositol-3-OH kinase/Akt pathway or mutation of the Akt site on eNOS protein (at serine 1177) attenuates the serine phosphorylation and prevents the activation of eNOS. Mimicking the phosphorylation of Ser 1177 directly enhances enzyme activity and alters the sensitivity of the enzyme to Ca2+, rendering its activity maximal at sub-physiological concentrations of Ca2+. Thus, phosphorylation of eNOS by Akt represents a novel Ca2+-independent regulatory mechanism for activation of eNOS.read more
Citations
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Journal ArticleDOI
AKT/PKB signaling: navigating downstream.
TL;DR: Those Akt substrates that are most likely to contribute to the diverse cellular roles of Akt, which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration are discussed.
Journal ArticleDOI
Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: A report of the International Brachial Artery Reactivity Task Force
Mary C. Corretti,Todd J. Anderson,Emelia J. Benjamin,David S. Celermajer,Francois Charbonneau,Mark A. Creager,John E. Deanfield,Helmut Drexler,Marie Gerhard-Herman,David M. Herrington,Patrick Vallance,Joseph A. Vita,Robert A. Vogel +12 more
TL;DR: State-of-the-art information is presented and insights are provided into the strengths and limitations of high-resolution ultrasonography of the brachial artery to evaluate vasomotor function, with guidelines for its research application in the study of endothelial physiology.
Journal ArticleDOI
Cellular survival: a play in three Akts
TL;DR: The mechanisms by which survival factors regulate the PI3K/c-Akt cascade, the evidence that activation of the PI 3K/ c-AKT pathway promotes cell survival, and the current spectrum of c- akt targets and their roles in mediating c- Akt-dependent cell survival are reviewed.
Journal ArticleDOI
Nitric oxide synthases: structure, function and inhibition
TL;DR: This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in the authors' understanding of this enzyme family.
Journal ArticleDOI
Prognostic Impact of Coronary Vasodilator Dysfunction on Adverse Long-Term Outcome of Coronary Heart Disease
TL;DR: Coronary endothelial vasodilator dysfunction predicts long-term atherosclerotic disease progression and cardiovascular event rates and can provide pivotal information as both a diagnostic and prognostic tool in patients at risk for coronary heart disease.
References
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Salvador Moncada,Annie Higgs +1 more
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TL;DR: It is demonstrated that activation of PKBalpha by insulin or insulin‐like growth factor‐1 (IGF‐1) results from phosphorylation of both Thr308 and Ser473, that phosphorylate of both residues is critical to generate a high level of P KBalpha activity and that the phosphorylated of Thr308 in vivo is not dependent on phosphorylations of Ser473 or vice versa.
Journal ArticleDOI
Mechanism of activation of protein kinase B by insulin and IGF-1.
Dario R. Alessi,Mirjana Andjelkovic,Barry Caudwell,Peter Cron,Nick Morrice,Philip Cohen,Brian A. Hemmings +6 more
TL;DR: In this paper, the activation of PKBalpha was accompanied by its phosphorylation at Thr308 and Ser473 and, like activation, likeactivation was prevented by the phosphatidylinositol 3-kinase inhibitor wortmannin.
Journal ArticleDOI
Flow-mediated endothelial mechanotransduction
TL;DR: The transmission of hemodynamic forces throughout the endothelium and the mechanotransduction mechanisms that lead to biophysical, biochemical, and gene regulatory responses of endothelial cells to hemodynamic shear stresses are reviewed.