TW-01, a piperazinedione-derived compound, inhibits Ras-mediated cell proliferation and angioplasty-induced vascular restenosis.
PURPOSE
Vascular smooth muscle cell (VSMC) proliferation plays a critical role in the pathogenesis of atherosclerosis and restenosis. This study investigated piperazinedione derived compound TW-01-mediated inhibitory effects on VSMC proliferation and intimal hyperplasia.


METHODS
Cell proliferation was determined using [(3)H]-thymidine incorporation and MTT assay; cell cycle distribution was measured using flow cytometry; proteins and mRNA expression were determined using western blotting and RT-PCR analyses; DNA binding activity of nuclear factor-κB (NF-κB), as measured using enzyme-linked immunosorbent assays (ELISA); in vivo effects of TW-01 were determined using balloon angioplasty in the rat.


RESULTS
TW-01 significantly inhibited cell proliferation. At the concentrations used, no cytotoxic effects were observed. Three predominant signaling pathways were inhibited by TW-01: (a) extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) activation and its downstream effectors of c-fos, c-jun, and c-myc; (b) DNA binding activity of nuclear factor-κB (NF-κB); and, (c) Akt/protein kinase B (PKB) and cell cycle progression. Furthermore, TW-01 also inhibited Ras activation, a shared upstream event of each of these signaling cascades. In vascular injury studies, oral administration of TW-01 significantly suppressed intimal hyperplasia induced by balloon angioplasty.


CONCLUSION
The present study suggests that TW-01 might be a potential candidate for atherosclerosis treatment.
['Lin|Chao-Feng|CF|', 'Huang|Han-Li|HL|', 'Peng|Chieh-Yu|CY|', 'Lee|Yu-Ching|YC|', 'Wang|Hui-Po|HP|', 'Teng|Che-Ming|CM|', 'Pan|Shiow-Lin|SL|']
D000800:Angioplasty, Balloon D000818:Animals D017536:Carotid Artery, Common D049109:Cell Proliferation D002470:Cell Survival D002478:Cells, Cultured D023903:Coronary Restenosis D000242:Cyclic AMP D006152:Cyclic GMP D054659:Diketopiperazines D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D006965:Hyperplasia D008297:Male D019950:Mitogen-Activated Protein Kinase 1 D048052:Mitogen-Activated Protein Kinase 3 D032389:Myocytes, Smooth Muscle D016328:NF-kappa B D011725:Pyridines D017208:Rats, Wistar D017539:Tunica Intima D018631:ras Proteins
TW-01 Proliferation Restenosis Vascular smooth muscle cell Atherosclerosis Angioplasty