The role of heat shock protein 90 in migration and proliferation of vascular smooth muscle cells in the development of atherosclerosis

J Mol Cell Cardiol. 2014 Jul;72:157-67. doi: 10.1016/j.yjmcc.2014.03.008. Epub 2014 Mar 18.

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.

Keywords: Atherosclerosis; Heat shock protein 90; Restenosis; Smooth muscle cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / cytology
  • Aorta / drug effects
  • Aorta / metabolism
  • Atherosclerosis / drug therapy
  • Atherosclerosis / etiology
  • Atherosclerosis / genetics*
  • Atherosclerosis / pathology
  • Benzoquinones / pharmacology*
  • Cell Cycle Checkpoints / drug effects
  • Cell Line
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cholesterol / administration & dosage
  • Cholesterol / adverse effects
  • Diet, High-Fat / adverse effects
  • Gene Expression Regulation
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • HSP90 Heat-Shock Proteins / genetics*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Lactams, Macrocyclic / pharmacology*
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism*
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism*
  • Plaque, Atherosclerotic / drug therapy
  • Plaque, Atherosclerotic / etiology
  • Plaque, Atherosclerotic / genetics*
  • Plaque, Atherosclerotic / pathology
  • Primary Cell Culture
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Signal Transduction
  • Triazoles / pharmacology

Substances

  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Receptors, LDL
  • STA 9090
  • Triazoles
  • tanespimycin
  • Cholesterol
  • Matrix Metalloproteinase 2