title: The role of heat shock protein 90 in migration and proliferation of vascular smooth muscle cells in the development of atherosclerosis.
abstract: The molecular chaperone heat shock protein 90 (HSP90) is overexpressed in plaques of atherosclerosis patients, and is associated with plaque instability. However, the role of HSP90 in atherosclerosis remains unclear. The present study investigated the effects of HSP90 inhibition on migration and proliferation of vascular smooth muscle cells (VSMCs) and involvement in atherosclerosis. To examine the role of HSP90 in VSMC migration, VSMCs were treated with the specific HSP90 inhibitors, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) and STA-9090. Results of a chemotaxis assay showed that the HSP90 inhibitors suppress migration of VSMCs. HSP90 inhibition also prevented invasion and sprout formation of VSMCs via inhibition of matrix metalloproteinase-2 proteolytic activity. Results of a flow cytometric analysis showed that HSP90 inhibition induces cell cycle arrest via regulation of cyclin D3, PCNA and pRb. To investigate the role of HSP90 in the development of atherosclerosis, low-density lipoprotein receptor (LDLR) deficient mice were fed with a high cholesterol diet for 4weeks and treated with 17-AAG for 8weeks. HSP90 inhibition suppressed migration of VSMCs into atherosclerotic plaque lesions in high cholesterol diet-stimulated LDLR(-/-) mice. Inhibition of HSP90 attenuates formation of atherosclerotic plaques via suppression of VSMC migration and proliferation, indicating that HSP90 inhibitors can be used as therapeutic agents for atherosclerosis and in stent restenosis.
authors.affiliation: Division of Life Sciences, Korea University, Seoul 136-701, South Korea.
authors.forename: Jeonghan
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Medicine, Graduate School, University of Ulsan, Seoul 138-736, South Korea.
authors.forename: Sung-Wuk
authors.initials: SW
authors.lastname: Jang
authors.affiliation: Division of Life Sciences, Korea University, Seoul 136-701, South Korea.
authors.forename: Eunsoo
authors.initials: E
authors.lastname: Park
authors.affiliation: Division of Life Sciences, Korea University, Seoul 136-701, South Korea.
authors.forename: Minseok
authors.initials: M
authors.lastname: Oh
authors.affiliation: Division of Life Sciences, Korea University, Seoul 136-701, South Korea.
authors.forename: Sodam
authors.initials: S
authors.lastname: Park
authors.affiliation: Division of Life Sciences, Korea University, Seoul 136-701, South Korea. Electronic address: jesangko@korea.ac.kr.
authors.forename: Jesang
authors.initials: J
authors.lastname: Ko
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D016227:Benzoquinones / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000008:administration & dosage / Q000009:adverse effects; D059305:Diet, High-Fat / Q000009:adverse effects; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000188:drug therapy / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D061251:Primary Cell Culture; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D014230:Triazoles / Q000494:pharmacology
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011973:Receptors, LDL; C533237:STA 9090; D014230:Triazoles; C112765:tanespimycin; D002784:Cholesterol; D020778:Matrix Metalloproteinase 2
keywords: Atherosclerosis; Heat shock protein 90; Restenosis; Smooth muscle cell