TY - JOUR
T1 - Mouse heat shock transcription factor 1 deficiency alters cardiac redox homeostasis and increases mitochondrial oxidative damage
AU - Yan, Liang Jun
AU - Christians, Elisabeth S.
AU - Liu, Li
AU - Xiao, Xian Zhong
AU - Sohal, Rajindar S.
AU - Benjamin, Ivor J.
PY - 2002/10/1
Y1 - 2002/10/1
N2 - In this study, using heat shock factor 1 (Hsf1) knock-out mice as a model, we tested the hypothesis that HSF1-dependent regulation of heat shock proteins (Hsps) is required to maintain redox state and attenuate oxidative damage in the normal heart. Here we report that, in mice, HSF1 deficiency reduces cardiac expression of Hsp25, αB-crystallin and Hsp70, but not Hsp60 and Hsp90. Consistent with the downregulation of Hsp25, for example, a significantly lower glutathione (GSH)/glutathione disulfate (GSSG) ratio was associated with the decreased activity, but not protein content, of glucose 6-phosphate dehydrogenase. Consequently, superoxide was generated at a higher rate, and several mitochondrial proteins, including adenine nucleotide translocase 1 (ANT1), were more oxidized by HSF1 deficiency in vivo. Oxidative damage to ANT1 protein, a structural component of the mitochondrial permeability transition pore (MPTP), decreases its catalytic activity and increases MPTP opening, respectively. Taken together, our results indicate for the first time that constitutive expression of HSP chaperones requires HSF1 activity, and that such HSF1-dependent requirements are directly and functionally linked to maintain redox homeostasis and antioxidative defenses at normal (37°C) temperature.
AB - In this study, using heat shock factor 1 (Hsf1) knock-out mice as a model, we tested the hypothesis that HSF1-dependent regulation of heat shock proteins (Hsps) is required to maintain redox state and attenuate oxidative damage in the normal heart. Here we report that, in mice, HSF1 deficiency reduces cardiac expression of Hsp25, αB-crystallin and Hsp70, but not Hsp60 and Hsp90. Consistent with the downregulation of Hsp25, for example, a significantly lower glutathione (GSH)/glutathione disulfate (GSSG) ratio was associated with the decreased activity, but not protein content, of glucose 6-phosphate dehydrogenase. Consequently, superoxide was generated at a higher rate, and several mitochondrial proteins, including adenine nucleotide translocase 1 (ANT1), were more oxidized by HSF1 deficiency in vivo. Oxidative damage to ANT1 protein, a structural component of the mitochondrial permeability transition pore (MPTP), decreases its catalytic activity and increases MPTP opening, respectively. Taken together, our results indicate for the first time that constitutive expression of HSP chaperones requires HSF1 activity, and that such HSF1-dependent requirements are directly and functionally linked to maintain redox homeostasis and antioxidative defenses at normal (37°C) temperature.
KW - HSF1
KW - Hsps
KW - Mitochondrial ANT1
KW - Oxidative damage
KW - Redox state
UR - http://www.scopus.com/inward/record.url?scp=0036790590&partnerID=8YFLogxK
U2 - 10.1093/emboj/cdf528
DO - 10.1093/emboj/cdf528
M3 - Article
C2 - 12356732
AN - SCOPUS:0036790590
SN - 0261-4189
VL - 21
SP - 5164
EP - 5172
JO - EMBO Journal
JF - EMBO Journal
IS - 19
ER -