Probucol mediates vascular remodeling after percutaneous transluminal angioplasty via down-regulation of the ERK1/2 signaling pathway.
Although probucol is known to prevent restenosis by regulating vascular remodeling after percutaneous transluminal coronary angioplasty, the mechanisms remain unclear. The present study was designed to investigate whether probucol mediates vascular remodeling via the extracellular signal-regulated kinase 1/2 (ERK1/2) signalling pathway. A rabbit restenosis model was used, in which the New Zealand white rabbits received angioplasty with a 3.5 F angioplasty balloon catheter and the proliferation and migration of smooth muscle cells (SMCs) was induced by oxidized low-density lipoprotein (ox-LDL). We evaluated several vascular remodeling parameters and found that probucol prevented lumen restenosis and mediated expansive remodeling with a remodeling index greater than 1 and that the proliferation and migration of SMCs was inhibited. Based on Western blot analyses, probucol decreased the expression of phospho-mitogen-activated protein kinase kinases 1 (p-MEK1) and phospho-ERK1/2 and enhanced the expression of mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) and caveolin-1. Cells treated with the MEK1 inhibitor PD98059 demonstrated a remarkable suppression of the effects of probucol. Furthermore, immunofluorescence analysis showed that probucol inhibited the activation of ERK1/2 by preventing its translocation to the nucleus. It was also found that c-myc expression in aortic tissue after angioplasty and the activator protein 1 (AP1) activity in SMCs induced by ox-LDL were decreased with probucol treatment. In conclusion, probucol mediated vascular remodeling to prevent restenosis after angioplasty by down-regulating the ERK1/2 signaling pathway.
Yang
Yun-Bo
YB
Department of Pharmacology, School of Pharmaceutical Science, Central South University, Changsha 410078, China.
Yang
Yi-Xin
YX
Su
Bo
B
Tang
Yun-Lian
YL
Zhu
Bing-Yang
BY
Hu
Zhuo-Wei
ZW
Li
Gui-Yuan
GY
Li
Yuan-Jian
YJ
Liao
Duan-Fang
DF
D000800:Angioplasty, Balloon; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051242:Caveolin 1 / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000517:prevention & control; D015536:Down-Regulation; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D016259:Genes, myc / Q000502:physiology; D006801:Humans; D006965:Hyperplasia / Q000188:drug therapy / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011341:Probucol / Q000494:pharmacology*; D011817:Rabbits; D013895:Thoracic Arteries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
D000975:Antioxidants; D051242:Caveolin 1; D018808:Transcription Factor AP-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D054638:Dual Specificity Phosphatase 1; D011341:Probucol