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Abstract-Release of free fatty acid (FFA) from adipose tissue is implicated in insulin resistance and endothelial dysfunction in patients with visceral fat obesity. We demonstrated previously that increased FFA levels cause endothelial dysfunction that is prevented by inhibition of the renin-angiotensin system (RAS) in humans. However, the mechanisms for FFA-mediated activation of RAS and the resultant endothelial dysfunction were not elucidated. We investigated effects of elevated FFA on activity of circulating and vascular RAS, angiotensin II-forming activity of leukocytes, and leukocyte activation of normotensive subjects. We showed that increased FFA levels significantly enhanced angiotensin II-forming activity in human mononuclear (mean fold increase: 3.5 at 180 minutes; Pϭ0.0016) and polymorphonuclear (2.0; Pϭ0.0012) cells, whereas parameters of the circulating and vascular RAS were not affected. We also showed that FFA caused angiotensin II-dependent leukocyte activation, which impaired endothelial function partly via increased myeloperoxidase release and presumably enhanced adhesion of leukocytes. We propose that the enhanced production of angiotensin II by FFA in mononuclear and polymorphonuclear cells causes activation of leukocytes that consequently impairs endothelial function. RAS in leukocytes may regulate the leukocyte-vasculature interaction as the mobile RAS in humans. T he levels of circulating free fatty acid (FFA), mainly originating from lipolysis in adipose tissue, are increased in patients with metabolic syndrome and type 2 diabetes mellitus, 1-3 reflecting resistance to the antilipolytic action of insulin. Increased plasma FFA concentrations cause endothelial dysfunction, 4 insulin resistance, 5 and endothelial apoptosis. 6 These observations, together with results from epidemiological studies, 7,8 suggest that FFA is involved in atherosclerosis in subjects with insulin resistance. Recently, we have found that FFA-induced endothelial dysfunction is prevented by the inhibition of the renin-angiotensin (Ang) system (RAS) in humans, 9 suggesting that RAS activation by FFA may predominantly contribute to FFA-induced endothelial dysfunction. This hypothesis appears plausible because of the close relationship between obesity and RAS activity in humans. 10,11 In addition, RAS activation is also associated with enhanced oxidative stress, 12 which is an intermediary mechanism by which FFA adversely alters vascular function. 13 However, although the proatherogenic action of excessive Ang II has been well documented, there is little information regarding the mechanism of RAS activation in individuals with obesity. Indeed, only a few studies have investigated the effects of elevated FFA on RAS activity. 14 The aim of the present study was to investigate effects of elevated FFA on RAS and to elucidate mechanisms for FFA-induced endothelial dysfunction in humans. We also investigated the interaction between FFA and leukocytes, because FFA is involved in leukocyte activation through protein kinase C re...

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