title: HSP90 inhibition by 17-DMAG attenuates oxidative stress in experimental atherosclerosis.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  Our results suggest that HSP90 inhibitors interfere with oxidative stress and modulate experimental atherosclerosis development through reduction in pro-oxidative factors.
authors.affiliation: Vascular Research Laboratory, IIS-Fundacion Jimenez Diaz, Autonoma University, Av. Reyes Católicos 2, Madrid, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Madrigal-Matute
authors.forename: Carlos Ernesto
authors.initials: CE
authors.lastname: Fernandez-Garcia
authors.forename: Carmen
authors.initials: C
authors.lastname: Gomez-Guerrero
authors.forename: Oscar
authors.initials: O
authors.lastname: Lopez-Franco
authors.forename: Begoña
authors.initials: B
authors.lastname: Muñoz-Garcia
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Blanco-Colio
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Martin-Ventura
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D016227:Benzoquinones / Q000494:pharmacology*; D002454:Cell Differentiation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D017382:Reactive Oxygen Species; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases