Abstract 1666: Enhanced Angiotensin II Forming Activity In Mononuclear Cell By Elevated Free Fatty Acid: Possible Implication in Endothelial Dysfunction as Mobile Renin-Angiotensin System
Objective -Free fatty acids (FFA) appear to be a pivotal adipocytokine that are closely associated with insulin resistance and endothelial dysfunction. We have previously shown that endothelial dysfunction evoked by elevated FFA was restored by the inhibition of renin-angiotensin system (RAS) without any involvement circulating RAS in human. In the present study we examined effect of elevated FFA on activity of circulating and local (forearm resistance vessels and blood cell) RAS in humans. We also examined effect s of elevated FFA and circulating ANG II on endothelial function in humans.
Methods-We measured plasma concentration of each component of circulating RAS, angiotensin II (Ang II) forming activities in mononuclear cells, and forearm blood flow (FBF) responses to intra-arterial infusions of Ang I and II before and after lipid/heparin infusion in 15 healthy males. We also measured changes in FBF during the infusions of acetylcholine as endothelial function before and after lipid infusion and ANG II infusion at 5 pmol/min. These experiments were repeated with the single dose of losartan.
Results -Elevated FFA did not affect plasma renin activity, serum ACE activity, plasma concentrations of ANG I, ANG II and aldosterone. Forearm vasoconstriction by either ANG I or II was not enhanced by elevated FFA. However, total (2250 and 11082 Ang II pmol/min/mg protein before and after lipid infusion respectively, p < 0.05), chymase- (853 and 2892, p < 0.01), and cathepsin G- (322 and, p < 0.05) dependent Ang II production in mononuclear cells were significantly increased after lipid/heparin infusion. Elevated FFA significantly impaired endothelial function, which was prevented by the single dose of losartan (50mg). However, intra-arterial infusion of Ang II did not affect endothelial function.
Conclusion-Elevated FFA by lipid/heparin infusion significantly enhanced Ang II forming activity in human mononuclear cells. However, elevated FFA did not increase any component of circulating RAS. Either sensitivity of forearm vessels to ANG II or vascular ANG II production, albeit assessed indirectly, was not affected by FFA. Activated RAS in mononuclear cells but not circulating ANG II may play an important role in FFA-induced endothelial dysfunction as “mobile” RAS.