Therapeutic potential of thiazolidinediones in activation of peroxisome proliferator-activated receptor gamma for monocyte recruitment and endothelial regeneration.
Thiazolidinediones, a new class of antidiabetic drugs that increase insulin sensitivity, have been shown to be ligands for peroxisome proliferator-activated receptor gamma (PPARgamma). Recent studies demonstrating that PPARgamma occurs in macrophages have focused attention on its role in macrophage functions. In this study, we investigated the effect of thiazolidinediones on monocyte proliferation and migration in vitro and the mechanisms involved. In addition, we examined the therapeutic potentials of thiazolidinediones for injured atherosclerotic lesions. Troglitazone and pioglitazone, the two thiazolidinediones, as well as 15-deoxy-delta12,14-prostaglandin J2 inhibited in a dose-dependent manner the serum-induced proliferation of THP-1 (human monocytic leukemia cells) and of U937 (human monoblastic leukemia cells), which permanently express PPARgamma. These ligands for PPARgamma also significantly inhibited migration of THP-1 induced by monocyte chemoattractant protein-1 (MCP-1). Troglitazone and 15-deoxy-delta12,14-prostaglandin J2 significantly suppressed the mRNA expression of the MCP family-specific receptor CCR2 (chemokine CCR2 receptor) in THP-1 at the transcriptional level. Furthermore, troglitazone significantly inhibited MCP-1 binding to THP-1. Oral administration of troglitazone to Watanabe heritable hyperlipidemic (WHHL) rabbits after balloon injury suppressed acute recruitment of monocytes/macrophages and accelerated re-endothelialization. These results suggest that thiazolidinediones have therapeutic potential for the treatment of diabetic vascular complications.
Tanaka
Tokuji
T
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Fukunaga
Yasutomo
Y
Itoh
Hiroshi
H
Doi
Kentaro
K
Yamashita
Jun
J
Chun
Tae-Hwa
TH
Inoue
Mayumi
M
Masatsugu
Ken
K
Saito
Takatoshi
T
Sawada
Naoki
N
Sakaguchi
Satsuki
S
Arai
Hiroshi
H
Nakao
Kazuwa
K
D000077556:Alitretinoin; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D001161:Arteriosclerosis / Q000517:prevention & control; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000293:injuries / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000235:genetics*; D000077205:Pioglitazone; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology; D000077288:Troglitazone; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D014945:Wound Healing / Q000187:drug effects
C097240:15-deoxy-delta(12,14)-prostaglandin J2; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D002839:Chromans; D047495:PPAR gamma; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D045162:Thiazolidinediones; D042461:Vascular Endothelial Growth Factor A; D000077556:Alitretinoin; D014212:Tretinoin; D000077288:Troglitazone; D015230:Prostaglandin D2; D000077205:Pioglitazone