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

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) c...

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Published in:Cardiovascular research 2012-07, Vol.95 (1), p.116-123
Main Authors: MADRIGAL-MATUTE, Julio, FERNANDEZ-GARCIA, Carlos Ernesto, GOMEZ-GUERRERO, Carmen, LOPEZ-FRANCO, Oscar, MUNOZ-GARCIA, Begona, EGIDO, Jesus, MIGUEL BLANCO-COLIO, Luis, MARTIN-VENTURA, Jose Luis
Format: Article
Language:English
Subjects:
Animals
Atherosclerosis (general aspects, experimental research)
Atherosclerosis - metabolism
Benzoquinones - pharmacology
Biological and medical sciences
Blood and lymphatic vessels
Cardiology. Vascular system
Cell Differentiation
Extracellular Signal-Regulated MAP Kinases - metabolism
HSP90 Heat-Shock Proteins - antagonists & inhibitors
Lactams, Macrocyclic - pharmacology
Macrophages - cytology
Male
Medical sciences
Mice
Muscle, Smooth, Vascular - drug effects
NADPH Oxidases - metabolism
Oxidative Stress - drug effects
Rats
Rats, Wistar
Reactive Oxygen Species - metabolism
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Summary: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. 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. Our results suggest that HSP90 inhibitors interfere with oxidative stress and modulate experimental atherosclerosis development through reduction in pro-oxidative factors.
ISSN:0008-6363
1755-3245
DOI:10.1093/cvr/cvs158