Endothelial nitric oxide synthase S1179 phosphorylation improves cerebral blood flow and reduces infarct size in focal cerebral ischemia

Kyoung Shin Hwa, Dmitriy N. Atochin, Sae Won Lee, Paul L. Huang, Michael A. Moskowitz, Cenk Ayata

Research output: Contribution to journalArticlepeer-review


Background and aims: Endothelial nitric oxide synthase (eNOS) is an important enzyme regulating vascular tone, platelet aggregation and inflammatory cell migration in cerebral ischemia. eNOS activity is regulated by multiple mechanisms; among these, eNOS phosphorylation appears to be an important regulatory step. Phosphorylation of eNOS at serine 1179 (S1179) by protein kinase Akt increases its catalytic activity at all intracellular calcium concentrations. S1179 phosphorylation is induced by a number of physiological stimuli such as shear stress, and inhibited in diabetes, hyperlipidemia, and hypertension, and thus appears to be critical in both physiological and disease states. However, the impact of eNOS phosphorylation on vascular function and disease pathogenesis has not been studied, in vivo. Methods: To determine the effect of eNOS S1179 phosphorylation on cerebral hemodynamic and metabolic response to ischemia, we subjected wild-type (WT, n=10), eNOS knockout (eNOS-/-, n=10), and transgenic mice expressing only phosphomimetic (S1179D, n=12) or unphosphorylatable (S1179A, n=11) mutant forms of eNOS (on eNOS-/- background) to distal or filament middle cerebral artery occlusion (dMCAO or fMCAO). Cerebral blood flow (CBF) was imaged non-invasively in ischemic core and penumbra using simultaneous laser speckle flowmetry. Results: Total eNOS protein expression was similar between S1179A and S1179D lines, although both transgenic lines had reduced eNOS expression compared to wild type littermates by western blotting. The S1179 phospho-eNOS was not detectable in brain or heart in either transgenic line. Mean arterial blood pressures were elevated in eNOS-/-, S1179A, and S1179D mice compared to WT (p

Original languageEnglish
JournalJournal of Cerebral Blood Flow and Metabolism
Issue numberSUPPL. 1
Publication statusPublished - 13 Nov 2007
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

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