Mouse heat shock transcription factor 1 deficiency alters cardiac redox homeostasis and increases mitochondrial oxidative damage.
In this study, using heat shock factor 1 (Hsf1) knockout 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, alphaB-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. Con sequently, 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 degrees C) temperature.
D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D006706:Homeostasis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D013367:Submitochondrial Particles / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D014157:Transcription Factors; D013481:Superoxides; D005954:Glucosephosphate Dehydrogenase; D005978:Glutathione; D019803:Glutathione Disulfide