Antiinflammatory and antiarteriosclerotic effects of pioglitazone.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands are widely used in patients with insulin resistance and diabetes. Because coronary artery disease is a major complication for such patients, it is important to determine the effects of PPARgamma activation on arteriosclerosis. Long-term inhibition of endothelial NO synthesis by administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) to rats induces coronary vascular inflammation (monocyte infiltration, monocyte chemoattractant protein-1 [MCP-1] expression) and subsequent arteriosclerosis. We examined the effects of pioglitazone (a PPARgamma ligand) in this rat model to determine whether PPARgamma activation with pioglitazone inhibits arteriosclerosis by its indirect effects on metabolic conditions or by direct effects on the cells participating to the pathogenesis of arteriosclerosis. We found that pioglitazone did not affect metabolic states, systolic blood pressure, or serum NO levels, but did prevent the L-NAME-induced coronary inflammation and arteriosclerosis. Pioglitazone did not reduce local expression of MCP-1 but markedly attenuated increased expression of the MCP-1 receptor C-C chemokine receptor 2 (CCR2) in lesional and circulating monocytes. PPARgamma activation with pioglitazone prevented coronary arteriosclerosis, possibly by its antiinflammatory effects (downregulation of CCR2 in circulating monocytes). Inhibition of the CCR2-mediated inflammation may represent novel antiinflammatory actions of pioglitazone beyond improvement of metabolic state.
Ishibashi
Minako
M
Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
Egashira
Kensuke
K
Hiasa
Ken-ichi
K
Inoue
Shujiro
S
Ni
Weihua
W
Zhao
Qingwei
Q
Usui
Makoto
M
Kitamoto
Shiro
S
Ichiki
Toshihiro
T
Takeshita
Akira
A
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D003324:Coronary Artery Disease / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; C515336:Ccr2 protein, rat; D018932:Chemokine CCL2; D007328:Insulin; D008055:Lipids; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D018160:Receptors, Cytoplasmic and Nuclear; C508962:Tgfb1 protein, rat; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D007703:Peptidyl-Dipeptidase A; D019331:NG-Nitroarginine Methyl Ester; D000077205:Pioglitazone