Inhibitory effect of fenofibrate on neointima hyperplasia via G(0)/G(1) arrest of cell proliferation.
We have previously reported that fenofibrate displayed a potent antithrombotic effect by the inhibition of platelet aggregation. The present study was designed to investigate the effects of fenofibrate on the neointimal hyperplasia and its possible molecular mechanism. Neointimal hyperplasia was measured in balloon-inflated-induced vascular injury model of male Sprague-Dawley rats and cell proliferation was measured in primary cultured rat aortic vascular smooth muscle cells (VSMCs). Fenofibrate-treated group showed a significant reduction in neointimal formation (0.07±0.04mm(2)) from the control (0.13±0.04mm(2)). Fenofibrate significantly inhibited platelet-derived growth factor (PDGF)-BB-induced cell counting and [(3)H]-thymidine incorporation into DNA. Fenofibrate suppressed the PDGF-BB-inducible progression through G(0)/G(1) to S phase of cell cycle. Moreover, fenofibrate inhibited not only phosphorylation of retinoblastoma (Rb) protein and expression of cyclin D/E, CDK 2/4 and proliferating cell nuclear antigen (PCNA) proteins but also mitogen-activated protein kinase (MAPK) signaling pathways such as ERK 1/2, p38 and JNK phosphorylation. In conclusion, the present study demonstrates that fenofibrate significantly inhibits neointimal formation via G(0)/G(1) arrest of PDGF-BB-induced cell proliferation in association with the inhibition of MAPK, which resulted in the downregulation of expressions of cyclin D/E, CDK 2/4 and PCNA proteins, suggesting that fenofibrate may be useful for individuals with a high risk of thrombotic or cardiovascular diseases.
Department of Pharmacology, College of Pharmacy & Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 305-764, Republic of Korea.
Jung-Jin
JJ
Lee
Ji-Yeon
JY
Yu
Wei-Yun
WY
Zhang
Tack-Joong
TJ
Kim
Yong
Y
Lim
Jin-Sook
JS
Kwon
Dong-Woon
DW
Kim
Chang-Seon
CS
Myung
Yeo-Pyo
YP
Yun
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects; D056741:Cyclin D / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D011345:Fenofibrate / Q000494:pharmacology* / Q000627:therapeutic use; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016193:G1 Phase / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006965:Hyperplasia / Q000150:complications; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058426:Neointima / Q000150:complications* / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*; D016160:Retinoblastoma Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D056741:Cyclin D; D019927:Cyclin E; D005343:Fibrinolytic Agents; D010982:Platelet-Derived Growth Factor; D018809:Proliferating Cell Nuclear Antigen; D020574:Proto-Oncogene Proteins c-sis; D016160:Retinoblastoma Protein; D000077214:Becaplermin; D004247:DNA; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D011345:Fenofibrate