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Activation of the stress protein response inhibits the STAT1 signaling pathway and iNOS function in alveolar macrophages: role of Hsp90 and Hsp70
Author(s) -
Howard Marybeth,
Roux Jeremie,
Lee Hyon,
Miyazawa Byron,
Lee JaeWoo,
Gartland Brandi,
Howard Amanda,
Matthay Michael,
Pittet JeanFrancois
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.673.4
Subject(s) - hsp90 , hsp70 , heat shock protein , microbiology and biotechnology , chemistry , hsp90 inhibitor , signal transduction , stat1 , biochemistry , biology , gene
Alveolar fluid clearance is impaired by iNOS/NO‐dependent mechanisms in ALI/ARDS. We investigated whether activation of the stress protein response (SPR) by heat, or using an Hsp90 inhibitor inhibits the STAT1 signaling pathway, which is activated in ALI/ARDS, and thus inhibits iNOS/NO production. Inhibition of STAT1 activation after heat stress results in detergent insolubilization of the STAT1 protein and its proteasomal degradation which is reversed with the pretreatment of cells with glycerol, a chemical chaperone that reduces the extent of heat‐induced protein denaturation. This early effect of SPR is the result of the disruption of the Hsp90 binding to the STAT1 protein and confirmed using an Hsp90 inhibitor. Recovery of STAT1 activation and iNOS synthesis occurs by 12 hours post‐SPR induction, however, NO production did not occur until 48 hours later. These results demonstrate a late effect of SPR activation involving the regulation of iNOS function by inducible Hsp70 (Hsp70i). Inhibiting Hsp70i expression after heat stress recovers iNOS function whereas overexpressing Hsp70i in the absence of heat stress inhibits iNOS function. These results represent novel mechanisms by which the activation of SPR inhibits STAT1 signaling in alveolar macrophages and highlight a potential clinical application for Hsp90 inhibitors in modulating NO signaling during the early phase of acute lung injury. [Research support: UCSF academic senate grant (MH); NIH GM62188 (JFP)]