Heat shock protein 90 inhibitors attenuate inflammatory responses in atherosclerosis

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78 Scopus citations

Abstract

AimsHeat shock protein 90 (HSP90) is a ubiquitous chaperone involved in the folding, activation, and assembly of many proteins. HSP90 inhibitors [17-allylamino-17-demethoxygeldamycin (17-AAG)/17-dimethyl aminothylamino-17- demethoxygeldanamycin hydrochloride (17-DMAG)] bind to and inactivate HSP90, increasing the heat shock response and suppressing different signalling pathways. We aim to investigate the effect of HSP90 inhibitors in the modulation of inflammatory responses during atherogenesis.Methods and resultsIn human atherosclerotic plaques, HSP90 immunostaining was increased in inflammatory regions and in plaques characterized by lower cap thickness. In cultured human macrophages and vascular smooth muscle cells, treatment with either 17-AAG or 17-DMAG increased HSP70 expression and reduced transcription factor [signal transducers and activators of transcription (STAT) and nuclear factor-B (NF-B)] activation and chemokine expression induced by proinflammatory cytokines. In vivo, hyperlipidaemic ApoE-/- mice were randomized to 17-DMAG (2 mg/kg every 2 days, n = 11) or vehicle injected (n = 9) during 10 weeks. Atherosclerotic plaques of mice treated with 17-DMAG displayed increased HSP70 expression and diminished NF-B and STAT activation, along with decreased lesion, lipid, and macrophage content, compared with vehicle-injected mice. In addition, treatment with 17-DMAG significantly reduced monocyte chemoattractant protein-1 levels, both in plaques and in plasma.ConclusionHSP90 expression is associated with features of plaque instability in advanced human lesions. HSP90 inhibitors reduce inflammatory responses in atherosclerosis, suggesting that HSP90 could be a novel therapeutic target in atherosclerosis.

Original languageEnglish (US)
Pages (from-to)330-337
Number of pages8
JournalCardiovascular research
Volume86
Issue number2
DOIs
StatePublished - May 1 2010
Externally publishedYes

Keywords

  • Atherosclerosis
  • Heat shock proteins
  • Inflammation

ASJC Scopus subject areas

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

Cite this

Heat shock protein 90 inhibitors attenuate inflammatory responses in atherosclerosis. / Madrigal-Matute, Julio; López-Franco, Oscar; Blanco-Colio, Luis Miguel; Muñoz-García, Begoña; Ramos-Mozo, Priscila; Ortega, Luis; Egido, Jesus; Martín-Ventura, Jose Luis.

In: Cardiovascular research, Vol. 86, No. 2, 01.05.2010, p. 330-337.

Research output: Contribution to journalArticle