Reciprocal Phosphorylation and Regulation of Endothelial Nitric-oxide Synthase in Response to Bradykinin Stimulation

Harris, M. Brennan; Ju, Hong; Venema, Virginia J.; Liang, Haiying; Zou, Rong; Michell, Belinda J.; Chen, Zhi Ping; Kemp, Bruce E.; Venema, Richard C.

doi:10.1074/jbc.m100229200

Cited by 339 publications

(305 citation statements)

References 32 publications

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“…9,10,23 Although bradykinin-induced phosphorylation of eNOS is partially dependent on the PI3K/Akt pathway, it has been suggested that eNOS regulation by GPCRs, such as B 2 -bradykinin receptor, is more dependent on calmodulin KII and a calcium-dependent pathway. 11 In contrast, our results clearly suggest that Ang-(1-7)…”

Section: Discussioncontrasting

confidence: 57%

“…Phosphorylation of eNOS at Ser1177 by agonists acting through G protein-coupled receptors is transient. 11,12 In contrast, our results indicate that the pronounced phosphorylation of Ser1177 in Ang-(1-7)-stimulated cells was sustained for Ն30 minutes, indicating possible long-lasting eNOS activation.…”

Section: Discussioncontrasting

confidence: 54%

“…Rapid changes in the phosphorylation of eNOS at these residues precede its activation in response to stimulation of endothelial cells with agonists such as bradykinin, histamine, estrogen, and ionomycin. 11,22,23 However, effects of Ang-(1-7) on eNOS phosphorylation and the role of Mas are unknown. Our data show for the first time that Ang-(1-7) regulates Ser1177/Thr495 phosphorylation and increases NO synthase activity and NO production.…”

Section: Discussionmentioning

confidence: 99%

“…eNOS phosphorylation at Ser1177 is a well-characterized pathway activated by vascular endothelial growth factor, 8 insulin-like growth factor-1, 9 fluid shear stress, 10 and bradykinin. 11 Phosphorylation also involves a decrease in the dependence of the enzyme for Ca-2ϩ -calmodulin. 12 In contrast, eNOS phosphorylation at threonine 495 reduces enzyme activity and NO generation.…”

mentioning

confidence: 99%

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Angiotensin-(1-7) Through Receptor Mas Mediates Endothelial Nitric Oxide Synthase Activation via Akt-Dependent Pathways

et al. 2007

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Abstract-Angiotensin-(1-7) [Ang-(1-7)] causes endothelial-dependent vasodilation mediated, in part, by NO release.However, the molecular mechanisms involved in endothelial NO synthase (eNOS) activation by Ang-(1-7) remain unknown. Using Chinese hamster ovary cells stably transfected with Mas cDNA (Chinese hamster ovary-Mas), we evaluated the underlying mechanisms related to receptor Mas-mediated posttranslational eNOS activation and NO release. We further examined the Ang-(1-7) profile of eNOS activation in human aortic endothelial cells, which constitutively express the Mas receptor. Chinese hamster ovary-Mas cells and human aortic endothelial cell were stimulated with Ang-(1-7; 10 Ϫ7 mol/L; 1 to 30 minutes) in the absence or presence of A-779 (10 Ϫ6 mol/L). Additional experiments were performed in the presence of the phosphatidylinositol 3-kinase inhibitor wortmannin (10 Ϫ6 mol/L). Changes in eNOS (at Ser1177/Thr495 residues) and Akt phosphorylation were evaluated by Western blotting. NO release was measured using both the fluorochrome 2,3-diaminonaphthalene and an NO analyzer. Ang-(1-7) significantly stimulated eNOS activation (reciprocal phosphorylation/dephosphorylation at Ser1177/Thr495) and induced a sustained Akt phosphorylation (PϽ0.05). Concomitantly, a significant increase in NO release was observed (2-fold increase in relation to control). These effects were blocked by A-779. Wortmannin suppressed eNOS activation in both Chinese hamster ovary-Mas and human aortic endothelial cells. Our findings demonstrate that Ang-(1-7), through Mas, stimulates eNOS activation and NO production via Akt-dependent pathways. These novel data highlight the importance of the Ang-(1-7)/Mas axis as a putative regulator of endothelial function. T he renin-angiotensin system is a crucial regulator of cardiovascular homeostasis. Most physiological effects of angiotensin (Ang) II are mediated via Ang II type 1 (AT 1 ) receptors (AT 1 R), with Ang II type 2 (AT 2 ) receptors (AT 2 R) counteracting AT 1 R actions. 1 Growing evidence indicates that the Ang peptide Ang-(1-7) plays an important role in the renin-angiotensin system. 2 This heptapeptide is formed by Ang-converting enzyme-dependent and Ang-converting enzyme-independent pathways. Much attention has been given recently to its formation through hydrolysis of Ang II by the ectoenzyme Ang-converting enzyme 2, which is present in many organs. 3 Ang-(1-7) opposes many Ang II-stimulated actions. Ang-(1-7), acting through the G protein-coupled receptor (GPCR) Mas, releases NO and prostaglandins causing vasodilation, inhibition of cell growth, and opposition of AT 1 R-mediated Ang II vasoconstrictor and proliferative effects. 2 Overactivity of the renin-angiotensin system, as observed in cardiovascular diseases, and the lack of balance among its peptides may reduce NO bioavailability leading to endothelial dysfunction. 4,5 NO plays a critical role in endothelial function, maintaining vasodilator tone, inhibiting platelet aggregation and adhesion, and modulating vascular smooth ...

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Section: Discussioncontrasting

confidence: 57%

Section: Discussioncontrasting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Angiotensin-(1-7) Through Receptor Mas Mediates Endothelial Nitric Oxide Synthase Activation via Akt-Dependent Pathways

et al. 2007

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“…Our data provide evidence that the activation of eNOS translocation may be obtained for a longer time than eNOS phosphorylation. Accordingly, it could recently be shown that receptormediated Ca 2 þ -dependent eNOS translocation first reaches the maximum after 5 min and it can stay up to 20 min; this is longer than our observation time (Prabhakar et al, 1998), while a transient phosphorylation of eNOS at Ser1177 is known for not more than 5 min (Harris et al, 2001). Besides excitation-contraction coupling, different myocardial cellular and intracellular targets of NO necessary for myocardial maintenance and function could be shown, such as nerve fibers, resistance vessels and capillaries, as well as mitochondria (for a review, see Bloch et al, 2001a).…”

Section: Discussioncontrasting

confidence: 49%

Mechanisms of β₃‐adrenoceptor‐induced eNOS activation in right atrial and left ventricular human myocardium

Brixius

Bloch

Pott

et al. 2004

British J Pharmacology

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1 b-adrenoceptors are important modulators of cardiac function. The present study investigated b 3 -adrenergic eNOS activation in human myocardium. 2 We measured nitric oxide (NO) liberation (diaminofluorescence) and signal transduction (immunohistochemistry, phosphorylation of eNOS Ser1177 , eNOS Thr495 , eNOS Ser114 , Akt/protein kinase B (Akt/PKB), and eNOS translocation) in human right atrial (RA, aortocoronary-bypass OP) and left ventricular nonfailing (LV, rejected donor hearts) myocardium after application of BRL 37344 (BRL), a preferential b 3 -adrenoceptor agonist. 3 In both RA and LV, BRL (10 ml) induced a liberation of NO. An eNOS activation via translocation was only observed in RA after application of BRL (10 mM). Yet, the NO liberation in both LV and RA was accompanied by phosphorylation of eNOS Ser1177 and Akt/PKB. BRL-induced eNOS phosphorylation was abolished by LY292004, a blocker of PI-3 kinase. eNOS-Ser 114 phosphorylation was unchanged in RA, but decreased in LV after b 3 -adrenergic stimulation. BRL did not alter phosphorylation of eNOS Thr495 . 4 In conclusion, receptor-dependent eNOS activation is differentially regulated in the human heart. In the left ventricle, eNOS activation via phosphorylation seems to be of major importance, whereas in human atrial myocardium eNOS translocation is the predominant mechanism induced by b 3 -adrenergic activation.

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Decreased eNOS Protein Expression in Involuting and Propranolol-Treated Hemangiomas

Dai

Hou²,

Buckmiller³

et al. 2012

Arch Otolaryngol Head Neck Surg

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Reciprocal Phosphorylation and Regulation of Endothelial Nitric-oxide Synthase in Response to Bradykinin Stimulation

Cited by 339 publications

References 32 publications

Angiotensin-(1-7) Through Receptor Mas Mediates Endothelial Nitric Oxide Synthase Activation via Akt-Dependent Pathways

Angiotensin-(1-7) Through Receptor Mas Mediates Endothelial Nitric Oxide Synthase Activation via Akt-Dependent Pathways

Mechanisms of β₃‐adrenoceptor‐induced eNOS activation in right atrial and left ventricular human myocardium

Decreased eNOS Protein Expression in Involuting and Propranolol-Treated Hemangiomas

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Reciprocal Phosphorylation and Regulation of Endothelial Nitric-oxide Synthase in Response to Bradykinin Stimulation

Cited by 339 publications

References 32 publications

Angiotensin-(1-7) Through Receptor Mas Mediates Endothelial Nitric Oxide Synthase Activation via Akt-Dependent Pathways

Angiotensin-(1-7) Through Receptor Mas Mediates Endothelial Nitric Oxide Synthase Activation via Akt-Dependent Pathways

Mechanisms of β3‐adrenoceptor‐induced eNOS activation in right atrial and left ventricular human myocardium

Decreased eNOS Protein Expression in Involuting and Propranolol-Treated Hemangiomas

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Mechanisms of β₃‐adrenoceptor‐induced eNOS activation in right atrial and left ventricular human myocardium