Inhibitory effect of fenofibrate on neointima hyperplasia via G(0)/G(1) arrest of cell proliferation.

Abstract

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.

• Authors: Jung-Jin Lee, Ji-Yeon Yu, Wei-Yun Zhang, Tack-Joong Kim, Yong Lim, Jin-Sook Kwon, Dong-Woon Kim, Chang-Seon Myung, Yeo-Pyo Yun
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 650 Issue 1 Pg. 342-9 (Jan 10 2011) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 21040719 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier B.V. All rights reserved.

Chemical References

• Cyclin D
• Cyclin E
• Fibrinolytic Agents
• Platelet-Derived Growth Factor
• Proliferating Cell Nuclear Antigen
• Proto-Oncogene Proteins c-sis
• Retinoblastoma Protein
• Becaplermin
• DNA
• Cyclin-Dependent Kinase 2
• Cyclin-Dependent Kinase 4
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• p38 Mitogen-Activated Protein Kinases
• Fenofibrate

Topics

• Angioplasty, Balloon (adverse effects)
• Animals
• Becaplermin
• Cell Proliferation (drug effects)
• Cyclin D (metabolism)
• Cyclin E (metabolism)
• Cyclin-Dependent Kinase 2 (metabolism)
• Cyclin-Dependent Kinase 4 (metabolism)
• DNA (biosynthesis)
• Enzyme Activation (drug effects)
• Fenofibrate (pharmacology, therapeutic use)
• Fibrinolytic Agents (pharmacology, therapeutic use)
• G1 Phase (drug effects)
• Gene Expression Regulation (drug effects)
• Hyperplasia (complications)
• Intracellular Space (drug effects, metabolism)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Male
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Muscle, Smooth, Vascular (drug effects, metabolism, pathology)
• Neointima (complications, drug therapy, etiology, pathology)
• Phosphorylation (drug effects)
• Platelet-Derived Growth Factor (pharmacology)
• Proliferating Cell Nuclear Antigen (metabolism)
• Proto-Oncogene Proteins c-sis
• Rats
• Rats, Sprague-Dawley
• Resting Phase, Cell Cycle (drug effects)
• Retinoblastoma Protein (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)