Free fatty acid causes leukocyte activation and resultant endothelial dysfunction through enhanced angiotensin II production in mononuclear and polymorphonuclear cells.
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; P=0.0016) and polymorphonuclear (2.0; P=0.0012) 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.
Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus School of Medicine, Okinawa, Japan.
Yoko
Y
Azekoshi
Takanori
T
Yasu
Saiko
S
Watanabe
Tatsuya
T
Tagawa
Satomi
S
Abe
Ken
K
Yamakawa
Yoshinari
Y
Uehara
Shinichi
S
Momomura
Hidenori
H
Urata
Shinichiro
S
Ueda
D000328:Adult; D000804:Angiotensin II / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D005217:Fat Emulsions, Intravenous / Q000008:administration & dosage; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D009504:Neutrophils / Q000378:metabolism*; D009765:Obesity / Q000097:blood* / Q000503:physiopathology; D012016:Reference Values; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D055815:Young Adult
D005217:Fat Emulsions, Intravenous; D005230:Fatty Acids, Nonesterified; D000804:Angiotensin II