title: Mechanical stress-induced heat shock protein 70 expression in vascular smooth muscle cells is regulated by Rac and Ras small G proteins but not mitogen-activated protein kinases.
abstract: -Previous studies have documented that acute elevation in blood pressure results in heat shock protein (hsp) 70-mRNA expression followed by hsp70-protein production in rat aortas. In this article, we provide evidence that mechanical forces evoke rapid activation of heat shock transcription factor (HSF) and hsp70 accumulation. In our study, Western blot analysis demonstrated that hsp70-protein induction peaked between 6 and 12 hours after treatment with cyclic stain stress (60 cycles/minute, up to 30% elongation). Elevated protein levels were preceded by hsp70-mRNA transcription, which was associated with HSF1 phosphorylation and activation stimulated by mechanical forces, suggesting that the response was regulated at the transcriptional level. Conditioned medium from cyclic strain-stressed vascular smooth muscle cells (VSMCs) did not result in HSF-DNA-binding activation. Furthermore, mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases, c-Jun NH(2)-terminal protein kinases or stress-activated protein kinases, and p38 MAPKs, were also highly activated in response to cyclic strain stress. Inhibition of extracellular signal-regulated kinase and p38-MAPK activation by their specific inhibitors (PD 98059 and SB 202190) did not influence HSF1 activation. Interestingly, VSMC lines stably expressing dominant-negative rac (rac N17) abolished hsp-protein production and HSF1 activation induced by cyclic strain stress, whereas a significant reduction of hsp70 expression was seen in ras N17-transfected VSMC lines. Thus, our findings demonstrate that cyclic strain stress-induced hsp70 expression is mediated by HSF1 activation and regulated by rac and ras GTP-binding proteins. Induction of hsp70 could be important in maintaining VSMC homeostasis during vascular remodeling in response to hemodynamic stimulation.
authors.affiliation: Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria. qingbo.xu@oeaw.ac.at
authors.forename: Q
authors.initials: Q
authors.lastname: Xu
authors.forename: G
authors.initials: G
authors.lastname: Schett
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Hu
authors.forename: G
authors.initials: G
authors.lastname: Wick
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D051381:Rats; D013314:Stress, Mechanical; D014157:Transcription Factors; D014158:Transcription, Genetic; D020744:rac GTP-Binding Proteins / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C000619709:Hsf1 protein, rat; D016877:Oxidants; D014157:Transcription Factors; D009599:Nitroprusside; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins; D018631:ras Proteins