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 journalArticlepeer-review

55 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

Keywords

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

ASJC Scopus subject areas

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

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