alitretinoin and Arteriosclerosis

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.

Topics: Alitretinoin; Angioplasty, Balloon; Animals; Aorta; Arteriosclerosis; Binding, Competitive; Cell Line; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemokine CCL2; Chromans; Dose-Response Relationship, Drug; Endothelium, Vascular; Gene Expression Regulation; Humans; Macrophages; Male; Monocytes; Pioglitazone; PPAR gamma; Prostaglandin D2; Rabbits; Receptors, CCR2; Receptors, Chemokine; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thiazolidinediones; Time Factors; Tretinoin; Troglitazone; Vascular Endothelial Growth Factor A; Wound Healing

The formation of foam cells from macrophages in the arterial wall is characterized by dramatic changes in lipid metabolism, including increased expression of scavenger receptors and the uptake of oxidized low-density lipoprotein (oxLDL). We demonstrate here that the nuclear receptor PPARgamma is induced in human monocytes following exposure to oxLDL and is expressed at high levels in the foam cells of atherosclerotic lesions. Ligand activation of the PPARgamma:RXRalpha heterodimer in myelomonocytic cell lines induces changes characteristic of monocytic differentiation and promotes uptake of oxLDL through transcriptional induction of the scavenger receptor CD36. These results reveal a novel signaling pathway controlling differentiation and lipid metabolism in monocytic cells, and suggest that endogenous PPARgamma ligands may be important regulators of gene expression during atherogenesis.

Topics: Alitretinoin; Animals; Arteriosclerosis; CD36 Antigens; Cell Differentiation; Dimerization; Foam Cells; HL-60 Cells; Humans; Ligands; Lipoproteins, LDL; Macrophages; Membrane Proteins; Mice; Mice, Transgenic; Monocytes; Promoter Regions, Genetic; Prostaglandin D2; Receptors, Cytoplasmic and Nuclear; Receptors, Immunologic; Receptors, Lipoprotein; Receptors, Retinoic Acid; Receptors, Scavenger; Retinoid X Receptors; Rosiglitazone; Scavenger Receptors, Class B; Signal Transduction; Thiazoles; Thiazolidinediones; Transcription Factors; Transcriptional Activation; Tretinoin