TY - JOUR
T1 - ROS-dependent Syk and Pyk2-mediated STAT1 activation is required for 15(S)-hydroxyeicosatetraenoic acid-induced CD36 expression and foam cell formation
AU - Kotla, Sivareddy
AU - Singh, Nikhlesh K.
AU - Traylor, James G.
AU - Wayne Orr, A.
AU - Rao, Gadiparthi N.
N1 - Funding Information:
This work was supported by Grants HL064165 and HL074860 to G.N.R. and HL098435 to A.W.O. from the National Heart, Lung, and Blood Institute of National Institutes of Health .
Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2014/11
Y1 - 2014/11
N2 - 15(S)-Hydroxyeicosatetraenoic acid (15(S)-HETE), the major 15-lipoxygenase 1/2 (15-LO1/2) metabolite of arachidonic acid (AA), induces CD36 expression through xanthine oxidase and NADPH oxidase-dependent ROS production and Syk and Pyk2-dependent STAT1 activation. In line with these observations, 15(S)-HETE also induced foam cell formation involving ROS, Syk, Pyk2, and STAT1-mediated CD36 expression. In addition, peritoneal macrophages from Western diet-fed ApoE-/-mice exhibited elevated levels of xanthine oxidase and NADPH oxidase activities, ROS production, Syk, Pyk2, and STAT1 phosphorylation, and CD36 expression compared to those from ApoE-/-:12/15-LO-/-mice and these events correlated with increased lipid deposits, macrophage content, and lesion progression in the aortic roots. Human atherosclerotic arteries also showed increased 15-LO1 expression, STAT1 phosphorylation, and CD36 levels as compared to normal arteries. Together, these findings suggest that 12/15-LO metabolites of AA, particularly 12/15(S)-HETE, might play a crucial role in atherogenesis by enhancing foam cell formation.
AB - 15(S)-Hydroxyeicosatetraenoic acid (15(S)-HETE), the major 15-lipoxygenase 1/2 (15-LO1/2) metabolite of arachidonic acid (AA), induces CD36 expression through xanthine oxidase and NADPH oxidase-dependent ROS production and Syk and Pyk2-dependent STAT1 activation. In line with these observations, 15(S)-HETE also induced foam cell formation involving ROS, Syk, Pyk2, and STAT1-mediated CD36 expression. In addition, peritoneal macrophages from Western diet-fed ApoE-/-mice exhibited elevated levels of xanthine oxidase and NADPH oxidase activities, ROS production, Syk, Pyk2, and STAT1 phosphorylation, and CD36 expression compared to those from ApoE-/-:12/15-LO-/-mice and these events correlated with increased lipid deposits, macrophage content, and lesion progression in the aortic roots. Human atherosclerotic arteries also showed increased 15-LO1 expression, STAT1 phosphorylation, and CD36 levels as compared to normal arteries. Together, these findings suggest that 12/15-LO metabolites of AA, particularly 12/15(S)-HETE, might play a crucial role in atherogenesis by enhancing foam cell formation.
KW - CD36
KW - Foam cell
KW - ROS
KW - STAT1
KW - Syk
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U2 - 10.1016/j.freeradbiomed.2014.08.007
DO - 10.1016/j.freeradbiomed.2014.08.007
M3 - Article
C2 - 25152235
AN - SCOPUS:84907224934
SN - 0891-5849
VL - 76
SP - 147
EP - 162
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -