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.
Methods and 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.