title: Interplay between HSP90 and Nrf2 pathways in diabetes-associated atherosclerosis.
abstract: BACKGROUND
  Oxidative stress and inflammation are determinant processes in the development of diabetic vascular complications. Heat shock protein 90 (HSP90) overexpression in atherosclerotic plaques plays a role in sustaining inflammatory mechanisms, and its specific inhibition prevents atherosclerosis. The present work investigates, in a mouse model of diabetes-driven atherosclerosis, whether atheroprotection by pharmacological HSP90 inhibition is accomplished by bolstering antioxidant defense mechanisms headed by nuclear factor erythroid-derived 2-like 2 (Nrf2).
  
  
  METHODS
  Streptozotocin-induced diabetic apolipoprotein E-deficient mice were randomized to receive vehicle or HSP90 inhibitor (17-dimethylaminoethylamino-17-demethoxygeldanamycin, 4mg/kg) for 10 weeks. Aortic root sections were analyzed for plaque size and composition, transcription factor activity, and expression of inflammatory and antioxidant markers. In vitro studies were performed in murine macrophages cultured under hyperglycemic conditions.
  
  
  RESULTS
  Treatment with HSP90 inhibitor promoted the activation of Nrf2 in the aortic tissue of diabetic mice (predominantly localized in macrophages and smooth muscle cells) and also in cultured cells. Nrf2 induction was associated with a concomitant inhibition of nuclear factor-κB (NF-κB) in atherosclerotic plaques, thus resulting in a significant reduction in lesion size and inflammatory component (leukocytes and cytokines). Furthermore, atheroprotection by HSP90 inhibition was linked to the induction of cytoprotective HSP70, antioxidant enzymes (heme oxygenase-1, superoxide dismutase and catalase) and autophagy machinery (LC3 and p62/SQSTM1) in aortic tissue.
  
  
  CONCLUSIONS
  HSP90 inhibition protects from atherosclerosis in experimental diabetes through the induction of Nrf2-dependent cytoprotective mechanisms, reinforcing its therapeutic potential.
authors.affiliation: Renal, Vascular and Diabetes Research Lab, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Spain. Electronic address: iolanda.lazaro@fjd.es.
authors.forename: Iolanda
authors.initials: I
authors.lastname: Lazaro
authors.affiliation: Renal, Vascular and Diabetes Research Lab, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Oguiza
authors.affiliation: Renal, Vascular and Diabetes Research Lab, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
authors.forename: Carlota
authors.initials: C
authors.lastname: Recio
authors.affiliation: Renal, Vascular and Diabetes Research Lab, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Lopez-Sanz
authors.affiliation: Renal, Vascular and Diabetes Research Lab, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Bernal
authors.affiliation: Renal, Vascular and Diabetes Research Lab, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.affiliation: Renal, Vascular and Diabetes Research Lab, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gomez-Guerrero
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology* / Q000503:physiopathology; D016227:Benzoquinones / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D058226:Plaque, Atherosclerotic / Q000209:etiology / Q000473:pathology; D013311:Streptozocin
chemical_list: D000975:Antioxidants; D001057:Apolipoproteins E; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D051267:NF-E2-Related Factor 2; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D013311:Streptozocin
keywords: Antioxidant defense; Aterosclerosis; Atherosclerosis; Autofagia; Autophagy; Defensa antioxidante; Diabetes; Heat shock protein 90; Nrf2; Proteína de choque térmico 90