title: Linoleic acid attenuates endothelium-derived relaxing factor production by suppressing cAMP-hydrolyzing phosphodiesterase activity.
abstract: BACKGROUND
  Linoleic acid (LA) promotes monocyte chemotaxis and cell adhesion molecules such as MCP-1 and VCAM-1, which contribute to atherosclerogenesis. These molecules are restrained by endothelium-derived relaxing factors (EDRFs), such as nitric oxide (NO) and prostaglandin I2 (PGI2). Hence, the expressions of MCP-1 and VCAM-1 upregulated by LA may be partly attributable to decreased EDRF production. However, effect of LA on EDRF production remains controversial.
  
  
  RESULTS
  The present study aimed to examine the effects of LA and other free fatty acids on EDRF production and the endothelial Ca(2+) responses that mediate EDRF production, using primary cultured porcine aortic endothelial cells (PAECs). LA at 0.1-5 μmol/L attenuated bradykinin (BK)-induced NO and PGI2 production while suppressing the BK-induced Ca(2+) response dose-dependently. The inhibitory effect of LA on the Ca(2+) response was eliminated by adenylate cyclase inhibitor SQ22536, boosted by cAMP-hydrolyzing phosphodiesterase (PDE) inhibitor, rolipram, and mimicked by plasma membrane permeable 8-bromo-cAMP. Moreover, LA was confirmed to dose-dependently increase intracellular cAMP levels and selectively inhibit cAMP-hydrolyzing PDE activity in vitro. In contrast, none of palmitic, stearic, or oleic acid affected BK-induced EDRF production or Ca(2+) responses, or induced intracellular cAMP accumulation.
  
  
  CONCLUSIONS
  LA induced intracellular cAMP accumulation by inhibiting cAMP-hydrolyzing PDE activity, thus resulting in attenuation of Ca(2+) responses and EDRF production in PAECs.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine.
authors.forename: Jiazhang
authors.initials: J
authors.lastname: Wei
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D045462:Endothelium-Dependent Relaxing Factors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis; D019787:Linoleic Acid / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis; D013552:Swine; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D018932:Chemokine CCL2; D045462:Endothelium-Dependent Relaxing Factors; D004791:Enzyme Inhibitors; D019010:Vascular Cell Adhesion Molecule-1; C017759:9-(tetrahydro-2-furyl)-adenine; D009569:Nitric Oxide; D019787:Linoleic Acid; D011464:Epoprostenol; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000225:Adenine