TY - JOUR
T1 - PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis
AU - Takata, Yasunori
AU - Liu, Joey
AU - Yin, Fen
AU - Collins, Alan R.
AU - Lyon, Christopher J.
AU - Lee, Chih Hao
AU - Atkins, Annette R.
AU - Downes, Michael
AU - Barish, Grant D.
AU - Evans, Ronald M.
AU - Hsueh, Willa A.
AU - Tangirala, Rajendra K.
PY - 2008/3/18
Y1 - 2008/3/18
N2 - Activation of the nuclear hormone receptor peroxisome proliferator- activated receptor δ (PPARδ) has been shown to improve insulin resistance, adiposity, and plasma HDL levels. However, its antiatherogenic role remains controversial. Here we report atheroprotective effects of PPARδ activation in a model of angiotensin II (AngII)-accelerated atherosclerosis, characterized by increased vascular inflammation related to repression of an antiinflammatory corepressor, B cell lymphoma-6 (Bcl-6), and the regulators of G protein-coupled signaling (RGS) proteins RGS4 and RGS5. In this model, administration of the PPARδ agonist GW0742 (1 or 10 mg/kg) substantially attenuated AngII-accelerated atherosclerosis without altering blood pressure and increased vascular expression of Bcl-6, RGS4, and RGS5, which was associated with suppression of inflammatory and atherogenic gene expression in the artery. In vitro studies demonstrated similar changes in AngII-treated macrophages: PPARδ activation increased both total and free Bcl-6 levels and inhibited AngII activation of MAP kinases, p38, and ERK1/2. These studies uncover crucial proinflammatory mechanisms of AngII and highlight actions of PPARδ activation to inhibit AngII signaling, which is atheroprotective.
AB - Activation of the nuclear hormone receptor peroxisome proliferator- activated receptor δ (PPARδ) has been shown to improve insulin resistance, adiposity, and plasma HDL levels. However, its antiatherogenic role remains controversial. Here we report atheroprotective effects of PPARδ activation in a model of angiotensin II (AngII)-accelerated atherosclerosis, characterized by increased vascular inflammation related to repression of an antiinflammatory corepressor, B cell lymphoma-6 (Bcl-6), and the regulators of G protein-coupled signaling (RGS) proteins RGS4 and RGS5. In this model, administration of the PPARδ agonist GW0742 (1 or 10 mg/kg) substantially attenuated AngII-accelerated atherosclerosis without altering blood pressure and increased vascular expression of Bcl-6, RGS4, and RGS5, which was associated with suppression of inflammatory and atherogenic gene expression in the artery. In vitro studies demonstrated similar changes in AngII-treated macrophages: PPARδ activation increased both total and free Bcl-6 levels and inhibited AngII activation of MAP kinases, p38, and ERK1/2. These studies uncover crucial proinflammatory mechanisms of AngII and highlight actions of PPARδ activation to inhibit AngII signaling, which is atheroprotective.
KW - Macrophage
KW - Peroxisome proliferator-activated receptor δ
KW - Vascular inflammation
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U2 - 10.1073/pnas.0708647105
DO - 10.1073/pnas.0708647105
M3 - Article
C2 - 18337495
AN - SCOPUS:41949123156
VL - 105
SP - 4277
EP - 4282
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 11
ER -