HSP90 inhibition by 17-DMAG attenuates oxidative stress in experimental atherosclerosis

Julio Madrigal-Matute, Carlos Ernesto Fernandez-Garcia, Carmen Gomez-Guerrero, Oscar Lopez-Franco, Begoña Muñoz-Garcia, Jesus Egido, Luis Miguel Blanco-Colio, Jose Luis Martin-Ventura

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Aims Reactive oxygen species (ROS) participate in atherogenesis through different mechanisms including oxidative stress and inflammation. Proteins implicated in both processes, such as mitogen-activated protein kinase kinase (MEK) and some NADPH oxidase (NOX) subunits, are heat shock protein-90 (HSP90) client proteins. In this work, we investigated the antioxidant properties of the HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in experimental atherosclerosis. Methods and results Treatment of ApoE -/- mice with 17-DMAG (2 mg/kg every 2 days for 10 weeks) decreased ROS levels and extracellular signal-regulated kinase (ERK) activation in aortic plaques compared with control animals. Accordingly, treatment of rat vascular smooth muscle cells (VSMCs) with 17-DMAG increased HSP27 and HSP70 and inhibited ERK activation. Interestingly, 17-DMAG diminished NADPH oxidase dependent ROS production in VSMCs and monocytes. In addition, a marked reduction in NADPH oxidase dependent ROS production was observed with HSP90siRNA and the opposite pattern with HSP70siRNA. 17-DMAG also diminished the expression of Nox1 and Nox organizer-1 (Noxo1) in VSMCs and monocytes. Interestingly, 17-DMAG was able to modulate ROS-induced monocyte to macrophage differentiation. Finally, higher expression of Nox1 and Noxo1 was found in the inflammatory region of human atherosclerotic plaques, colocalizing with VSMCs, macrophages, and ROS-producing cells. Conclusion Our results suggest that HSP90 inhibitors interfere with oxidative stress and modulate experimental atherosclerosis development through reduction in pro-oxidative factors. Published on behalf of the European Society of Cardiology. All rights reserved.

Original languageEnglish (US)
Pages (from-to)116-123
Number of pages8
JournalCardiovascular research
Volume95
Issue number1
DOIs
StatePublished - Jul 1 2012
Externally publishedYes

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Keywords

  • Atherosclerosis
  • HSP90 inhibitors
  • Nox1
  • Noxo1
  • Oxidative stress

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Madrigal-Matute, J., Fernandez-Garcia, C. E., Gomez-Guerrero, C., Lopez-Franco, O., Muñoz-Garcia, B., Egido, J., Blanco-Colio, L. M., & Martin-Ventura, J. L. (2012). HSP90 inhibition by 17-DMAG attenuates oxidative stress in experimental atherosclerosis. Cardiovascular research, 95(1), 116-123. https://doi.org/10.1093/cvr/cvs158