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Oleanolic acid induces relaxation and calcium‐independent release of endothelium‐derived nitric oxide
Author(s) -
RodriguezRodriguez R,
Stankevicius E,
Herrera M D,
Østergaard L,
Andersen M R,
RuizGutierrez V,
Simonsen U
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.289
Subject(s) - oleanolic acid , calcium , nitric oxide , endothelium , endothelial stem cell , mesenteric arteries , chemistry , biochemistry , thapsigargin , endocrinology , medicine , biology , endoplasmic reticulum , alternative medicine , pathology , artery , in vitro
Background and purpose: The present study investigated the mechanisms by which oleanolic acid, a component of olive oil, increases release of nitric oxide (NO). Experimental approach: Measurements of isometric tension, NO concentration, or endothelial cell calcium were made in rat isolated mesenteric arteries. Immunoblotting for endothelial NOS (eNOS) and Akt kinase were performed in primary cultures of human umbilical vein endothelial cells (HUVECs). Key results: Oleanolic acid (3–30 μ M ) evoked endothelium‐dependent relaxations in noradrenaline‐contracted rat superior and small mesenteric arteries. In rat superior mesenteric arteries, oleanolic acid induced simultaneous increases in NO concentration and relaxation, and these responses were inhibited by an inhibitor of NOS, asymmetric dimethyl‐ L ‐arginine (300 μ M ) and by the NO scavenger, oxyhaemoglobin (10 μ M ). Oleanolic acid‐evoked NO increases were not reduced in Ca 2+ ‐free solution and in the presence of an inhibitor of endoplasmic reticulum calcium‐ATPase, thapsigargin (1 μ M ). Oleanolic acid evoked relaxation without changes in endothelial cell calcium, but decreased smooth muscle calcium in arterial segments. Oleanolic acid failed to increase calcium in HUVECs, but increased time‐dependently phosphorylation of Akt kinase at Serine 473 (Akt‐Ser 473 ) and eNOS at Serine 1177 (eNOS‐Ser 1177 ), which was attenuated by inhibitors of phosphoinositide‐3‐kinase. Conclusions and implications: This study provides direct evidence that a component of olive oil, oleanolic acid, activated endothelium‐dependent release of NO and decreased smooth muscle cell calcium followed by relaxation. The oleanolic acid‐evoked endothelium‐derived NO release was independent of endothelial cell calcium and involved phosphoinositide‐3‐kinase‐dependent phosphorylation of Akt‐Ser 473 followed by phosphorylation of eNOS‐Ser 1177 . British Journal of Pharmacology (2008) 155 , 535–546; doi: 10.1038/bjp.2008.289 ; published online 14 July 2008