Patterns of gene expression associated with recovery and injury in heat-stressed rats

BMC Genomics

Jaques Reifman⁴  John A Lewis⁶  Lisa R Leon³  David A Jackson¹  Bryan G Helwig³  William E Dennis⁶  Christine E Baer⁵  Vineet Rakesh⁴  Danielle L Ippolito²  Jonathan D Stallings⁶ 

[1]Pulmonary Health Program, U.S. Army Center for Environmental Health Research, Fort Detrick, Maryland

[2]Oak Ridge Institute for Science and Education, Fort Detrick, Maryland

[3]Thermal Mountain Medicine Division, U.S. Army Research Institute of Environmental Medicine, Natick, Massachusetts

[4]DoD Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland

[5]Excet, Inc., Fort Detrick, Maryland

[6]Environmental Health Program, U.S. Army Center for Environmental Health Research, Bldg. 568 Doughten Drive, MD 21702-5010 Fort Detrick, Maryland

关键词: Protein aggregation;    Systems biology;    Proteomics;    Transcriptomics;    Heat stress;   

Others  :  1089893
DOI  :  10.1186/1471-2164-15-1058

 received in 2014-06-06, accepted in 2014-11-24,  发布年份 2014

【 摘 要 】

Background

The in vivo gene response associated with hyperthermia is poorly understood. Here, we perform a global, multiorgan characterization of the gene response to heat stress using an in vivo conscious rat model.

Results

We heated rats until implanted thermal probes indicated a maximal core temperature of 41.8°C (T_c,Max). We then compared transcriptomic profiles of liver, lung, kidney, and heart tissues harvested from groups of experimental animals at T_c,Max, 24 hours, and 48 hours after heat stress to time-matched controls kept at an ambient temperature. Cardiac histopathology at 48 hours supported persistent cardiac injury in three out of six animals. Microarray analysis identified 78 differentially expressed genes common to all four organs at T_c,Max. Self-organizing maps identified gene-specific signatures corresponding to protein-folding disorders in heat-stressed rats with histopathological evidence of cardiac injury at 48 hours. Quantitative proteomics analysis by iTRAQ (isobaric tag for relative and absolute quantitation) demonstrated that differential protein expression most closely matched the transcriptomic profile in heat-injured animals at 48 hours. Calculation of protein supersaturation scores supported an increased propensity of proteins to aggregate for proteins that were found to be changing in abundance at 24 hours and in animals with cardiac injury at 48 hours, suggesting a mechanistic association between protein misfolding and the heat-stress response.

Conclusions

Pathway analyses at both the transcript and protein levels supported catastrophic deficits in energetics and cellular metabolism and activation of the unfolded protein response in heat-stressed rats with histopathological evidence of persistent heat injury, providing the basis for a systems-level physiological model of heat illness and recovery.

【 授权许可】

   
2014 Stallings et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Becker JA, Stewart LK: Heat-related illness. Am Fam Physician 2011, 83(11):1325-1330.
• [2]Bouchama A, Knochel JP: Heat stroke. N Engl J Med 2002, 346(25):1978-1988.
• [3]Epstein Y, Roberts WO: The pathopysiology of heat stroke: an integrative view of the final common pathway. Scand J Med Sci Sports 2011, 21(6):742-748.
• [4]Wenger RH: Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J 2002, 16(10):1151-1162.
• [5]Winkenwerder M, Sawka MN: Disorders due to heat and cold. In Cecil Medicine. 23rd edition. Edited by Goldman L, Ausiello D. Philadelphia: Elsevier Science; 2007:763-767.
• [6]Lanner JT, Georgiou DK, Dagnino-Acosta A, Ainbinder A, Cheng Q, Joshi AD, Chen ZW, Yarotskyy V, Oakes JM, Lee CS, Monroe TO, Sabtillan A, Dong K, Goodyear L, Ismailov II, Rodney GG, Dirksen RT, Hamilton SL: AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation. Nat Med 2012, 18(2):244-251.
• [7]Leon LR, Helwig BG: Heat stroke: role of the systemic inflammatory response. J Appl Physiol Respir Environ Exerc Physiol 2010, 109(6):1980-1988.
• [8]Leon LR, Helwig BG: Role of endotoxin and cytokines in the systemic inflammatory response to heat injury. Front Biosci 2010, 2:916-938.
• [9]Grogan H, Hopkins PM: Heat stroke: implications for critical care and anaesthesia. Br J Anaesth 2002, 88(5):700-707.
• [10]Kregel KC: Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. J Appl Physiol Respir Environ Exerc Physiol 2002, 92(5):2177-2186.
• [11]Moran DS, Eli-Berchoer L, Heled Y, Mendel L, Schocina M, Horowitz M: Heat intolerance: does gene transcription contribute? J Appl Physiol Respir Environ Exerc Physiol 2006, 100(4):1370-1376.
• [12]Parsell DA, Lindquist S: The function of heat-shock proteins in stress tolerance: degradation and reactivation of damaged proteins. Annu Rev Genet 1993, 27:437-496.
• [13]Parsell DA, Taulien J, Lindquist S: The role of heat-shock proteins in thermotolerance. Philos Trans R Soc Lond B Biol Sci 1993, 339(1289):279-285. discussion 285–276
• [14]Zhang HJ, Drake VJ, Morrison JP, Oberley LW, Kregel KC: Selected contribution: differential expression of stress-related genes with aging and hyperthermia. J Appl Physiol Respir Environ Exerc Physiol 2002, 92(4):1762-1769. discussion 1749
• [15]Sonna LA, Wenger CB, Flinn S, Sheldon HK, Sawka MN, Lilly CM: Exertional heat injury and gene expression changes: a DNA microarray analysis study. J Appl Physiol Respir Environ Exerc Physiol 2004, 96(5):1943-1953.
• [16]Sonna LA, Glueck SB, Jeunemaitre X: Exercise, genetics, and blood pressure: focus on "physical exercise and blood pressure with reference to the angiotensinogen M235T polymorphism" and on "angiotensinogen M235T polymorphism associates with exercise hemodynamics in postmenopausal women". Physiol Genomics 2002, 10(2):45-47.
• [17]Sonna LA, Gaffin SL, Pratt RE, Cullivan ML, Angel KC, Lilly CM: Effect of acute heat shock on gene expression by human peripheral blood mononuclear cells. J Appl Physiol Respir Environ Exerc Physiol 2002, 92(5):2208-2220.
• [18]Sonna LA, Fujita J, Gaffin SL, Lilly CM: Invited review: effects of heat and cold stress on mammalian gene expression. J Appl Physiol Respir Environ Exerc Physiol 2002, 92(4):1725-1742.
• [19]Horowitz M, Eli-Berchoer L, Wapinski I, Friedman N, Kodesh E: Stress-related genomic responses during the course of heat acclimation and its association with ischemic-reperfusion cross-tolerance. J Appl Physiol Respir Environ Exerc Physiol 2004, 97(4):1496-1507.
• [20]Rakesh V, Stallings JD, Helwig BG, Leon LR, Jackson DA, Reifman J: A 3-D mathematical model to identify organ-specific risks in rats during thermal stress. J Appl Physiol 2013, 5(12):1822-1837.
• [21]Horowitz M: Genomics and proteomics of heat acclimation. Front Biosci 2010, 2:1068-1080.
• [22]Islam A, Deuster PA, Devaney JM, Ghimbovschi S, Chen Y: An exploration of heat tolerance in mice utilizing mRNA and microRNA expression analysis. PLoS One 2013, 8(8):e72258.
• [23]Ha K, Coulombe-Huntington J, Majewski J: Comparison of affymetrix gene array with the exon array shows potential application for detection of transcript isoform variation. BMC Genomics 2009, 10:519. BioMed Central Full Text
• [24]Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA: DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 2003, 4(5):3. BioMed Central Full Text
• [25]Huang J, Wang H, Xie X, Gao H, Guo G: Developmental changes in DNA methylation of pollen mother cells of David lily during meiotic prophase I. Mol Biol 2010, 44(5):853-858.
• [26]Leverette RD, Andrews MT, Maxwell ES: Mouse U14 snRNA is a processed intron of the cognate hsc70 heat shock pre-messenger RNA. Cell 1992, 71(7):1215-1221.
• [27]Chen MS, Goswami PC, Laszlo A: Differential accumulation of U14 snoRNA and hsc70 mRNA in Chinese hamster cells after exposure to various stress conditions. Cell Stress Chaperones 2002, 7(1):65-72.
• [28]Brocker C, Thompson DC, Vasiliou V: The role of hyperosmotic stress in inflammation and disease. Biomol Concepts 2012, 3(4):345-364.
• [29]Lotz GP, Lin H, Harst A, Obermann WM: Aha1 binds to the middle domain of Hsp90, contributes to client protein activation, and stimulates the ATPase activity of the molecular chaperone. J Biol Chem 2003, 278(19):17228-17235.
• [30]Gerstner JR, Landry CF: The zinc-binding protein chordc1 undergoes complex diurnal changes in mRNA expression during mouse brain development. Neurochem Res 2007, 32(2):241-250.
• [31]Gano JJ, Simon JA: A proteomic investigation of ligand-dependent HSP90 complexes reveals CHORDC1 as a novel ADP-dependent HSP90-interacting protein. Mol Cell Proteomics 2010, 9(2):255-270.
• [32]Pavithra L, Mukherjee S, Sreenath K, Kar S, Sakaguchi K, Roy S, Chattopadhyay S: SMAR1 forms a ternary complex with p53-MDM2 and negatively regulates p53-mediated transcription. J Mol Biol 2009, 388(4):691-702.
• [33]Pavithra L, Singh S, Sreenath K, Chattopadhyay S: Tumor suppressor SMAR1 downregulates Cytokeratin 8 expression by displacing p53 from its cognate site. Int J Biochem Cell Biol 2009, 41(4):862-871.
• [34]Pavithra L, Sreenath K, Singh S, Chattopadhyay S: Heat-shock protein 70 binds to a novel sequence in 5' UTR of tumor suppressor SMAR1 and regulates its mRNA stability upon Prostaglandin A2 treatment. FEBS Lett 2010, 584(6):1187-1192.
• [35]Schultz CR, Golembieski WA, King DA, Brown SL, Brodie C, Rempel SA: Inhibition of HSP27 alone or in combination with pAKT inhibition as therapeutic approaches to target SPARC-induced glioma cell survival. Mol Cancer 2012, 11:20. BioMed Central Full Text
• [36]Oehrl W, Cotsiki M, Panayotou G: Differential regulation of M3/6 (DUSP8) signaling complexes in response to arsenite-induced oxidative stress. Cell Signal 2013, 25(2):429-438.
• [37]Bauer H, Willert J, Koschorz B, Herrmann BG: The t complex-encoded GTPase-activating protein Tagap1 acts as a transmission ratio distorter in mice. Nat Genet 2005, 37(9):969-973.
• [38]Kuchta K, Knizewski L, Wyrwicz LS, Rychlewski L, Ginalski K: Comprehensive classification of nucleotidyltransferase fold proteins: identification of novel families and their representatives in human. Nucleic Acids Res 2009, 37(22):7701-7714.
• [39]Xu X, Zeng W, Popov S, Berman DM, Davignon I, Yu K, Yowe D, Offermanns S, Muallem S, Wilkie TM: RGS proteins determine signaling specificity of Gq-coupled receptors. J Biol Chem 1999, 274(6):3549-3556.
• [40]Rother S, Clausing E, Kieser A, Strasser K: Swt1, a novel yeast protein, functions in transcription. J Biol Chem 2006, 281(48):36518-36525.
• [41]Zhao W, Wang L, Zhang M, Wang P, Yuan C, Qi J, Meng H, Gao C: Tripartite motif-containing protein 38 negatively regulates TLR3/4- and RIG-I-mediated IFN-beta production and antiviral response by targeting NAP1. J Immunol 2012, 188(11):5311-5318.
• [42]Bernales S, McDonald KL, Walter P: Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol 2006, 4(12):e423.
• [43]Fujita E, Kouroku Y, Isoai A, Kumagai H, Misutani A, Matsuda C, Hayashi YK, Momoi T: Two endoplasmic reticulum-associated degradation (ERAD) systems for the novel variant of the mutant dysferlin: ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II). Hum Mol Genet 2007, 16(6):618-629.
• [44]Hoyer-Hansen M, Jaattela M: Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ 2007, 14(9):1576-1582.
• [45]Kamimoto T, Shoji S, Hidvegi T, Mizushima N, Umebayashi K, Perlmutter DH, Yoshimori T: Intracellular inclusions containing mutant alpha1-antitrypsin Z are propagated in the absence of autophagic activity. J Biol Chem 2006, 281(7):4467-4476.
• [46]Kouroku Y, Fujita E, Tanida I, Ueno T, Isoai A, Kumagai H, Ogawa S, Kaufman RJ, Kominami E, Momoi T: ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ 2007, 14(2):230-239.
• [47]Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, Shiosaka S, Hammarback JA, Urano F, Imaizumi K: Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 2006, 26(24):9220-9231.
• [48]Yorimitsu T, Nair U, Yang Z, Klionsky DJ: Endoplasmic reticulum stress triggers autophagy. J Biol Chem 2006, 281(40):30299-30304.
• [49]Chakrabarti A, Chen AW, Varner JD: A review of the mammalian unfolded protein response. Biotechnol Bioeng 2011, 108(12):2777-2793.
• [50]Morimoto RI: The heat shock response: systems biology of proteotoxic stress in aging and disease. Cold Spring Harb Symp Quant Biol 2011, 76:91-99.
• [51]Morimoto RI, Driessen AJ, Hegde RS, Langer T: The life of proteins: the good, the mostly good and the ugly. Nat Struct Mol Biol 2011, 18(1):1-4.
• [52]Fonseca SG, Burcin M, Gromada J, Urano F: Endoplasmic reticulum stress in beta-cells and development of diabetes. Curr Opin Pharmacol 2009, 9(6):763-770.
• [53]Glembotski CC: Endoplasmic reticulum stress in the heart. Circ Res 2007, 101(10):975-984.
• [54]Seigneuric R, Mjahed H, Gobbo J, Joly AL, Berthenet K, Shirley S, Garrido C: Heat shock proteins as danger signals for cancer detection. Front Biol 2011, 1:37.
• [55]Kampinga HH, Hageman J, Vos MJ, Kubota H, Tanguay RM, Bruford EA, Cheetham ME, Chen B, Hightower LE: Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones 2009, 14(1):105-111.
• [56]Macario AJ, Conway de Macario E: The pathology of cellular anti-stress mechanisms: a new frontier. Stress 2004, 7(4):243-249.
• [57]Gallucci S, Matzinger P: Danger signals: SOS to the immune system. Curr Opin Immunol 2001, 13(1):114-119.
• [58]Park HS, Lee JS, Huh SH, Seo JS, Choi EJ: Hsp72 functions as a natural inhibitory protein of c-Jun N-terminal kinase. EMBO J 2001, 20(3):446-456.
• [59]Cvoro A, Korac A, Matic G: Intracellular localization of constitutive and inducible heat shock protein 70 in rat liver after in vivo heat stress. Mol Cell Biochem 2004, 265(1–2):27-35.
• [60]Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G: Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell Cycle 2006, 5(22):2592-2601.
• [61]Didelot C, Lanneau D, Brunet M, Joly AL, De Thonel A, Chiosis G, Garrido C: Anti-cancer therapeutic approaches based on intracellular and extracellular heat shock proteins. Curr Med Chem 2007, 14(27):2839-2847.
• [62]Dehbi M, Baturcam E, Eldali A, Ahmed M, Kwaasi A, Chishti MA, Bouchama A: Hsp-72, a candidate prognostic indicator of heatstroke. Cell Stress Chaperones 2010, 15(5):593-603.
• [63]Beere HM: Death versus survival: functional interaction between the apoptotic and stress-inducible heat shock protein pathways. J Clin Invest 2005, 115(10):2633-2639.
• [64]Johnson JD, Fleshner M: Releasing signals, secretory pathways, and immune function of endogenous extracellular heat shock protein 72. J Leukoc Biol 2006, 79(3):425-434.
• [65]Wang ZZ, Wang CL, Wu TC, Pan HN, Wang SK, Jiang JD: Autoantibody response to heat shock protein 70 in patients with heatstroke. Am J Med 2001, 111(8):654-657.
• [66]Galloway E, Shin T, Huber N, Eismann T, Kuboki S, Schuster R, Blanchard J, Wong HR, Lentsch AB: Activation of hepatocytes by extracellular heat shock protein 72. Am J Physiol Cell Physiol 2008, 295(2):C514-520.
• [67]Salari S, Seibert T, Chen YX, Hu T, Shi C, Zhao X, Cuerrier CM, Raizman JE, O'Brien ER: Extracellular HSP27 acts as a signaling molecule to activate NF-kappaB in macrophages. Cell Stress Chaperones 2013, 18(1):53-63.
• [68]Thompson MR, Xu D, Williams BR: ATF3 transcription factor and its emerging roles in immunity and cancer. J Mol Med 2009, 87(11):1053-1060.
• [69]Lu D, Wolfgang CD, Hai T: Activating transcription factor 3, a stress-inducible gene, suppresses Ras-stimulated tumorigenesis. J Biol Chem 2006, 281(15):10473-10481.
• [70]Gilchrist M, Thorsson V, Li B, Rust AG, Korb M, Roach JC, Kennedy K, Hai T, Bolouri H, Aderem A: Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature 2006, 441(7090):173-178.
• [71]Hartman MG, Lu D, Kim ML, Kociba GJ, Shukri T, Buteau J, Wang X, Frankel WL, Guttridge D, Prentki M, Grey ST, Ron D, Hai T: Role for activating transcription factor 3 in stress-induced beta-cell apoptosis. Mol Cell Biol 2004, 24(13):5721-5732.
• [72]Horowitz M: Heat acclimation and cross-tolerance against novel stressors: genomic-physiological linkage. Prog Brain Res 2007, 162:373-392.
• [73]Horowitz M, Robinson SD: Heat shock proteins and the heat shock response during hyperthermia and its modulation by altered physiological conditions. Prog Brain Res 2007, 162:433-446.
• [74]Karper JC, de Jager SC, Ewing MM, de Vries MR, Bot I, van Santbrink PJ, Redeker A, Mallat Z, Binder CJ, Arens R, Jukema JW, Kuiper J, Quax PH: An unexpected intriguing effect of toll-like receptor regulator RP105 (CD180) on atherosclerosis formation with alterations on B-cell activation. Arterioscler Thromb Vasc Biol 2013, 33(12):2810-2817.
• [75]Karper JC, Ewing MM, de Vries MR, de Jager SC, Peters EA, de Boer HC, van Zonneveld AJ, Kuiper J, Huizinga EG, Brondijk TH, Kuiper J, Quax PH: TLR accessory molecule RP105 (CD180) is involved in post-interventional vascular remodeling and soluble RP105 modulates neointima formation. PLoS One 2013, 8(7):e67923.
• [76]Balch WE, Morimoto RI, Dillin A, Kelly JW: Adapting proteostasis for disease intervention. Science 2008, 319(5865):916-919.
• [77]Dobson CM: Protein folding and misfolding. Nature 2003, 426(6968):884-890.
• [78]Querfurth HW, LaFerla FM: Alzheimer's disease. N Engl J Med 2010, 362(4):329-344.
• [79]Selkoe DJ: Alzheimer's disease. Cold Spring Harb Perspect Biol 2011, 3:7.
• [80]Ciryam P, Tartaglia GG, Morimoto RI, Dobson CM, Vendruscolo M: Widespread aggregation and neurodegenerative diseases are associated with supersaturated proteins. Cell Rep 2013, 5(3):781-790.
• [81]Pan YX, Lin L, Ren AJ, Pan XJ, Chen H, Tang CS, Yuan WJ: HSP70 and GRP78 induced by endothelin-1 pretreatment enhance tolerance to hypoxia in cultured neonatal rat cardiomyocytes. J Cardiovasc Pharmacol 2004, 44(Suppl 1):S117-120.
• [82]Pan YX, Ren AJ, Zheng J, Rong WF, Chen H, Yan XH, Wu C, Yuan WJ, Lin L: Delayed cytoprotection induced by hypoxic preconditioning in cultured neonatal rat cardiomyocytes: role of GRP78. Life Sci 2007, 81(13):1042-1049.
• [83]Sun FC, Wei S, Li CW, Chang YS, Chao CC, Lai YK: Localization of GRP78 to mitochondria under the unfolded protein response. Biochem J 2006, 396(1):31-39.
• [84]Davies B, Morris T: Physiological parameters in laboratory animals and humans. Pharm Res 1993, 10(7):1093-1095.
• [85]Qu Y, He F, Chen Y: Different effects of the probe summarization algorithms PLIER and RMA on high-level analysis of Affymetrix exon arrays. BMC Bioinformatics 2010, 11:211. BioMed Central Full Text
• [86]Bourgon R, Gentleman R, Huber W: Independent filtering increases detection power for high-throughput experiments. Proc Natl Acad Sci U S A 2010, 107(21):9546-9551.
• [87]Hochberg Y, Benjamini Y: More powerful procedures for multiple significance testing. Stat Med 1990, 9(7):811-818.
• [88]Reiner A, Yekutieli D, Benjamini Y: Identifying differentially expressed genes using false discovery rate controlling procedures. Bioinformatics 2003, 19(3):368-375.
• [89]Eng JK, McCormack AL, Yates JR: An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein database. J Am Soc Mass Spectrom 1994, 5(11):976-989.
• [90]Nesvizhskii AI, Keller A, Kolker E, Aebersold R: A statistical model for identifying proteins by tandem mass spectrometry. Anal Chem 2003, 75(17):4646-4658.
• [91]Shadforth IP, Dunkley TP, Lilley KS, Bessant C: i-Tracker: for quantitative proteomics using iTRAQ. BMC Genomics 2005, 6:145. BioMed Central Full Text
• [92]Ahn JM, Sung HJ, Yoon YH, Kim BG, Yang WS, Lee C, Park HM, Kim BJ, Kim BG, Lee SY, An HJ, Cho JY: Integrated glycoproteomics demonstrates fucosylated serum paraoxonase 1 alterations in small cell lung cancer. Mol Cell Proteomics 2014, 13(1):30-48.
• [93]Silva JC, Gorenstein MV, Li GZ, Vissers JP, Geromanos SJ: Absolute quantification of proteins by LCMSE: a virtue of parallel MS acquisition. Mol Cell Proteomics 2006, 5(1):144-156.
• [94]Scholten A, Heck JR: Determining protein concentrations of the human ventricular proteome. In Heart Proteomics: Methods and Protocols. Volume 1005. Edited by Vivanco F. New York: Springer Science+Business Media; 2013:11-24.