BRADYKININ SIGNALING IN REGULATION OF eNOS

  • Venema, Richard C, (PI)

Project: Research project

Description

DESCRIPTION (provided by applicant): Endothelium-derived nitric oxide (NO) has a crucial role in regulation of the state of vasodilation of blood vessels and hence in regulation of blood pressure. Furthermore, because NO regulates this and a number of other important vascular processes, abnormalities in vascular NO production are thought to contribute to the pathogenesis of certain vascular disorders such as those of atherosclerosis, diabetes, and hypertension. NO is synthesized in endothelial cells by oxidation of L-arginine in a reaction catalyzed by the enzyme, endothelial nitric oxide synthase (eNOS). Recent investigations in several laboratories have established a role for Ser-1179 phosphorylation and Thr-497 dephosphorylation in agonist regulation of eNOS activity in endothelial cells. Data presented in the Preliminary Studies section of this proposal provide evidence for two additional sites of eNOS phosphorylation at Ser-617 and Ser-635. Our preliminary data shows that these two sites are transiently phosphorylated in cultured endothelial cells in response to stimulation with the eNOS-activating agonists bradykinin (BK), ATP, and vascular endothelial growth factor. The principal aim of the present proposal is to examine the hypothesis that eNOS activity in vascular endothelial cells is regulated in part by BK-stimulated phosphorylation of the enzyme at Ser-617 and Ser-635. Additional aims are to elucidate the molecular mechanism(s) by which phosphorylation at Ser-617 and Ser-635 alters enzyme catalytic activity and to test the hypothesis that phosphorylation at Ser-617 or Ser-635 alters eNOS protein-protein interactions with caveolin-1, the bradykinin B2 receptor, or heat shock protein 90. Finally, we will examine whether certain pathophysiological conditions, such as hyperglycemia or oxidative stress, alter either basal or BK-stimulated phosphorylation of eNOS at Ser-617 or Ser-635.
StatusFinished
Effective start/end date3/15/032/28/08

Funding

  • National Institutes of Health: $286,000.00
  • National Institutes of Health: $286,000.00
  • National Institutes of Health: $279,279.00
  • National Institutes of Health: $311,250.00

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Nitric Oxide Synthase Type III
Bradykinin
Phosphorylation
Blood Vessels
Nitric Oxide
Endothelial Cells
Enzymes
Bradykinin B2 Receptors
HSP90 Heat-Shock Proteins
Caveolin 1
Vasodilation
Hyperglycemia
Vascular Endothelial Growth Factor A
Arginine
Cultured Cells
Atherosclerosis
Proteins
Oxidative Stress
Adenosine Triphosphate
Blood Pressure

Keywords

  • Medicine(all)