TY - JOUR
T1 - HSP90 inhibition by 17-DMAG attenuates oxidative stress in experimental atherosclerosis
AU - Madrigal-Matute, Julio
AU - Fernandez-Garcia, Carlos Ernesto
AU - Gomez-Guerrero, Carmen
AU - Lopez-Franco, Oscar
AU - Muñoz-Garcia, Begoña
AU - Egido, Jesus
AU - Blanco-Colio, Luis Miguel
AU - Martin-Ventura, Jose Luis
N1 - Funding Information:
This work was supported by the Spanish Ministerio de Ciencia y Tecno-logía (SAF 2010-21852), Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Redes RECAVA (RD06/0014/0035), Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (PI10/00072), Sociedad Española de Aterosclerosis, and Lilly.
PY - 2012/7/1
Y1 - 2012/7/1
N2 - 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.
AB - 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.
KW - Atherosclerosis
KW - HSP90 inhibitors
KW - Nox1
KW - Noxo1
KW - Oxidative stress
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U2 - 10.1093/cvr/cvs158
DO - 10.1093/cvr/cvs158
M3 - Article
C2 - 22547655
AN - SCOPUS:84862905692
SN - 0008-6363
VL - 95
SP - 116
EP - 123
JO - Cardiovascular research
JF - Cardiovascular research
IS - 1
ER -