Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice.
The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that regulates fat-cell development and glucose homeostasis and is the molecular target of a class of insulin-sensitizing agents used for the management of type 2 diabetes mellitus. PPARgamma is highly expressed in macrophage foam cells of atherosclerotic lesions and has been demonstrated in cultured macrophages to both positively and negatively regulate genes implicated in the development of atherosclerosis. We report here that the PPARgamma-specific agonists rosiglitazone and GW7845 strongly inhibited the development of atherosclerosis in LDL receptor-deficient male mice, despite increased expression of the CD36 scavenger receptor in the arterial wall. The antiatherogenic effect in male mice was correlated with improved insulin sensitivity and decreased tissue expression of TNF-alpha and gelatinase B, indicating both systemic and local actions of PPARgamma. These findings suggest that PPARgamma agonists may exert antiatherogenic effects in diabetic patients and provide impetus for efforts to develop PPARgamma ligands that separate proatherogenic activities from antidiabetic and antiatherogenic activities.
Li
A C
AC
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093-0651, USA.
Brown
K K
KK
Silvestre
M J
MJ
Willson
T M
TM
Palinski
W
W
Glass
C K
CK
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D001483:Base Sequence; D018955:CD36 Antigens / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007333:Insulin Resistance; D008024:Ligands; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010080:Oxazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D000077154:Rosiglitazone; D051122:Scavenger Receptors, Class B; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
D018955:CD36 Antigens; D017931:DNA Primers; D008024:Ligands; D008565:Membrane Proteins; D010080:Oxazoles; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; C401311:GW 7845; D014443:Tyrosine; D020780:Matrix Metalloproteinase 9