Thiazolidinediones, peroxisome proliferator-activated receptor γ agonists, regulate endothelial cell growth and secretion of vasoactive peptides

Insulin resistance has been highlighted as a common causal factor for glucose intolerance, hypertension and dyslipidemia, all of which are cardiovascular risk factors. A new class of antidiabetic agents, thiazolidinediones (TZDs), has been developed and demonstrated to improve insulin sensitivity. TZDs are high affinity ligands for peroxisome proliferator-activated receptor γ (PPARγ), the crucial transcription factor for adipocytes. Recent studies showed that PPARγ is also expressed in monocytes/macrophages and is suggested to be involved in atherosclerosis. We could detect PPARγ gene transcript in several cultured endothelial cells (human aortic endothelial cells (HAoECs), human coronary artery endothelial cells (HCAECs), human umbilical vein endothelial cells (HUVECs) and bovine carotid artery endothelial cells (BAECs)) as well as human coronary arteries we examined. Since endothelial dysfunction is critical for atherosclerosis, we investigated the effects of TZDs, troglitazone (TRO) and pioglitazone (PIO), on endothelial cell growth and secretion of C-type natriuretic peptide (CNP), which we demonstrated as a novel endothelium-derived relaxing peptide, and endothelin (ET), a potent vasoconstrictor, using HAoECs, HCAECs, HUVECs and BAECs. When all these cultured endothelial cells were daily treated with TRO and PIO for 5 days, both TRO and PIO (10^-8 M) significantly stimulated ³H-thymidine incorporation of all these endothelial cells. In contrast, higher dose of TRO and PIO (10^-5 M) significantly suppressed DNA synthesis. TRO and PIO also exerted the compatible effect on the increase of cell numbers. TRO and PIO significantly enhanced CNP secretion from BAECs. In contrast, ET secretion from BAECs was suppressed by both TRO and PIO in a dose-dependent manner. The results of the present study suggest that TZDs modulate endothelial functions, including regulation of endothelial cell growth and secretion of endothelium-derived vasoactive substances, which affect vascular tone and remodeling in the process of atherosclerosis.