Upregulation of Cytoprotective Chaperones Mediate Better Tolerance to High Altitude

  • Richa Rathor
  • Geetha SuryakumarEmail author
Part of the Heat Shock Proteins book series (HESP, volume 16)


Disturbance in redox homeostasis at high altitude due to hypobaric hypoxia has been implicated in several physiological as well as pathological consequences. A shift in the redox potential leads to modulation of key biological cascades which are intricately regulated by proteins. Enhanced oxidative protein modifications at high altitude trigger several protective responses such as the heat shock response or the unfolded protein response to restore the protein homeostasis thus counteracting the stress and promoting cell survival. Upregulation of heat shock response enhanced hypoxic tolerance and better survival under low oxygen tensions. Modulation of proteostasis by upregulation of heat shock proteins and concomitant protein quality control mechanisms play a very important role in differential tolerance or susceptibility to environmental hypoxia. Hence, the present work potentiate the use of proteostasis modulators either chemical or herbal which can be developed as therapeutic interventions for the treatment of a multitude of hypoxia related pathophysiologies.


Chaperones Chaperokine ER stress High altitude HSP70 Tolerance 



4-Phenyl butyric acid


5-Aminoimidazole-4-carboxamide ribonucleotide


AMP-activated protein kinase


Mammalian target of rapamycin


Non-alcoholic fatty liver disease


Protein kinase A


Tauroursodeoxycholic acid


Unfolded protein response



The authors are thankful to Dr. Bhuvnesh Kumar, Director, DIPAS, for his constant support and encouragement.The study was supported by the Defence Research and Development Organisation, Ministry of Defence, Government of India.


  1. Adewoye AH, Klings ES, Farber HW, Palaima E, Bausero MA, McMahon L, Odhiambo A, Surinder S, Yoder M, Steinberg MH, Asea A (2005) Sickle cell vaso-occlusive crisis induces the release of circulating serum heat shock protein-70. Am J Hematol 78:240–242PubMedPubMedCentralCrossRefGoogle Scholar
  2. Agrawal A, Rathor R, Suryakumar G (2017) Oxidative protein modification alters proteostasis under acute hypobaric hypoxia in skeletal muscles: a comprehensive in vivo study. Cell Stress Chap 22:429–443CrossRefGoogle Scholar
  3. Akerfelt M, Trouillet D, Mezger V, Sistonen L (2007) Heat shock factors at a crossroad between stress and development. Ann N Y Acad Sci 1113:15–27PubMedCrossRefPubMedCentralGoogle Scholar
  4. Alhusaini S, McGee K, Schisano B, Harte A, McTernan P, Kumar S, Tripathi G (2010) Lipopolysaccharide, high glucose and saturated fatty acids induce endoplasmic reticulum stress in cultured primary human adipocytes: salicylate alleviates this stress. Biochem Biophys Res Commun 397:472–478PubMedCrossRefPubMedCentralGoogle Scholar
  5. Anckar J, Sistonen L (2007) Heat shock factor 1 as a coordinator of stress and developmental pathways. Adv Exp Med Biol 594:78–88PubMedCrossRefPubMedCentralGoogle Scholar
  6. Arnold-Schild D, Hanau D, Spehner D, Schmid C, Rammensee HG, de la Salle H, Schild H (1999) Receptor mediated endocytosis of heat shock proteins by professional antigen-presenting cells. J Immunol 162:3757–3760Google Scholar
  7. Asea A (2008) Hsp70: a chaperokine. Novartis Found Symp 291:173–179 discussion 179–83, 221–4PubMedCrossRefPubMedCentralGoogle Scholar
  8. Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo GC, Calderwood SK (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 6:435–442PubMedPubMedCentralCrossRefGoogle Scholar
  9. Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277:15028–15034PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bachar-Wikstrom E, Wikstrom JD, Kaiser N, Cerasi E, Leibowitz G (2013) Improvement of ER stress-induced diabetes by stimulating autophagy. Autophagy 9:626–628PubMedPubMedCentralCrossRefGoogle Scholar
  11. Baeuerle PA, Baltimore D (1988) I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science 242:540–546PubMedCrossRefPubMedCentralGoogle Scholar
  12. Basseri S, Lhotak S, Sharma AM, Austin RC (2009) The chemical chaperone 4-phenylbutyrate inhibits adipogenesis by modulating the unfolded protein response. J Lip Res 50:2486–2501CrossRefGoogle Scholar
  13. Beissinger M, Buchner J (1998) How chaperones fold proteins. Biol Chem 379(3):245–259PubMedPubMedCentralGoogle Scholar
  14. Brewer JW, Diehl JA (2000) PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proc Natl Acad Sci 97:12625–12630PubMedCrossRefPubMedCentralGoogle Scholar
  15. Brinkmeier H, Ohlendieck K (2014) Chaperoning heat shock proteins: proteomic analysis and relevance for normal and dystrophin-deficient muscle. Proteom Clin Appl 8:875–895CrossRefGoogle Scholar
  16. Brot N, Weissbach H (1982) The biochemistry of methionine sulfoxide residues in proteins. Trends Biochem Sci 7(4):137–139CrossRefGoogle Scholar
  17. Butterfield DA, Stadtman ER (1997) Protein oxidation processes in aging brain. Adv Cell Aging Gerontol 2:161–191CrossRefGoogle Scholar
  18. Calfon M, Zeng H, Urano F, Till JH, Hubbard SR (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415:92–96PubMedCrossRefPubMedCentralGoogle Scholar
  19. Campisi J, Leem TH, Fleshner M (2003) Stress-induced extracellular Hsp72 is a functionally significant danger signal to the immune system. Cell Stress Chap 8(3):272–286CrossRefGoogle Scholar
  20. Capeillere-Blandin C, Gausson V, Descamps-Latscha B, Witko-Sarsat V (2004) Biochemical and spectrophotometric significance of advanced oxidized protein products. Biochim Biophys Acta 1689:91–102PubMedCrossRefPubMedCentralGoogle Scholar
  21. Chakrabarti A, Chen AW, Varner JD (2011) A review of the mammalian unfolded protein response. Biotechnol Bioeng 108:2777–2793PubMedPubMedCentralCrossRefGoogle Scholar
  22. Cunha DA, Ladriere L, Ortis F, Igoillo-Esteve M, Gurzov EN, Lupi R, Marchetti P, Eizirik DL, Cnop M (2009) Glucagon-like peptide-1 agonists protect pancreatic β-cells from lipotoxic endoplasmic reticulum stress through upregulation of BiP and JunB. Diabetes 58:2851–2862PubMedPubMedCentralCrossRefGoogle Scholar
  23. Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R (2003) Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta 329:23–38PubMedCrossRefPubMedCentralGoogle Scholar
  24. Davies KJ (1987) Protein damage and degradation by oxygen radicals. I general aspects. J Biol Chem 262(20):9895–9901PubMedPubMedCentralGoogle Scholar
  25. Faiss R, Pialoux V, Sartori C, Faes C, Deriaz O, Millet GP (2013) Ventilation, oxidative stress, and nitric oxide in hypobaric versus normobaric hypoxia. Med Sci Sports Exerc 45:253–260PubMedCrossRefPubMedCentralGoogle Scholar
  26. Fu S, Yang L, Li P, Hofmann O, Dicker L, Hide W, Lin X, Watkins SM, Ivanov AR, Hotamisligil GS (2011) Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473:528–531PubMedPubMedCentralCrossRefGoogle Scholar
  27. Gelfi C, De Palma S, Ripamonti M, Eberini I, Wait R, Bajracharya A, Marconi C, Schneider A, Hoppeler H, Cerretelli P (2004) New aspects of altitude adaptation in Tibetans: a proteomic approach. FASEB J 18:612–614PubMedCrossRefPubMedCentralGoogle Scholar
  28. Georgopoulos C, Welch WJ (1993) Role of the major heat shock proteins as molecular chaperones. Annu Rev Cell Biol 9:601–634PubMedCrossRefPubMedCentralGoogle Scholar
  29. Gross C, Hansch D, Gastpar R, Multhoff G (2003) Interaction of heat shock protein 70 peptide with NK cells involves the NK receptor CD94. Biol Chem 384:267–279CrossRefGoogle Scholar
  30. Gurd JW, Bissoon N, Beesley PW, Nakazawa T, Yamamoto T, Vannucci SJ (2002) Differential effects of hypoxia-ischemia on subunit expression and tyrosine phosphorylation of the NMDA receptor in 7- and 21-day-old rats. J Neurochem 82:848–856PubMedCrossRefPubMedCentralGoogle Scholar
  31. Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic reticulum-resident kinase. Nature 397:271–274PubMedCrossRefPubMedCentralGoogle Scholar
  32. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099–1108PubMedCrossRefPubMedCentralGoogle Scholar
  33. Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, Sabatini DD, Ron D (2001) Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol Cell 7:1153–1163PubMedCrossRefPubMedCentralGoogle Scholar
  34. Hartl FU (1996) Molecular chaperones in cellular protein folding. Nature 381:571–580CrossRefPubMedGoogle Scholar
  35. Haslbeck M (2002) sHSP and their role in the chaperone network. Cell Mol Life Sci 59:1649–1657PubMedCrossRefPubMedCentralGoogle Scholar
  36. Haze K, Yoshida H, Yanagi H, Yura T, Mori K (1999) Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 10:3787–3799PubMedPubMedCentralCrossRefGoogle Scholar
  37. Herbst R, Schafer U, Seckler R (1997) Equilibrium intermediates in the reversible unfolding of firefly (Photinus pyralis) luciferase. J Biol Chem 272:7099–7105PubMedCrossRefPubMedCentralGoogle Scholar
  38. Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13:89–102PubMedPubMedCentralCrossRefGoogle Scholar
  39. Horowitz S, Koldewey P, Stull F, Bardwell JCA (2017) Folding while bound to chaperones. Curr Opin Struct Biol 48:1–5PubMedCrossRefPubMedCentralGoogle Scholar
  40. Hotamisligil GS (2010) Endoplasmic reticulum stress and atherosclerosis. Nat Med 16:396–399PubMedPubMedCentralCrossRefGoogle Scholar
  41. Jain K, Suryakumar G, Prasad R, Ganju L (2013a) Upregulation of cytoprotective defense mechanisms and hypoxia-responsive proteins imparts tolerance to acute hypobaric hypoxia. High Alt Med Biol 14:65–77PubMedCrossRefPubMedCentralGoogle Scholar
  42. Jain K, Suryakumar G, Prasad R, Singh SN, Ganju L (2013b) Myocardial ER chaperone activation and protein degradation occurs due to synergistic, not individual, cold and hypoxic stress. Biochimie 95(10):1897–1908PubMedCrossRefPubMedCentralGoogle Scholar
  43. Jain K, Suryakumar G, Ganju L, Singh SB (2014) Differential hypoxic tolerance is mediated by activation of heat shock response and nitric oxide pathway. Cell Stress Chap 19:801–812CrossRefGoogle Scholar
  44. Jain K, Suryakumar G, Ganju L, Singh SB (2016a) Amelioration of ER stress by phenylbutyric acid reduces chronic hypoxia induced cardiac damage and improves hypoxic tolerance through upregulation of HIF-1α. Vasc Pharmacol 83:36–46CrossRefGoogle Scholar
  45. Jain K, Suryakumar G, Prasad R, Ganju L, Singh SB (2016b) Enhanced hypoxic tolerance by Seabuckthorn is due to upregulation of HIF-1a and attenuation of ER stress. J Appl Biomed 14(1):71–83CrossRefGoogle Scholar
  46. Jee H (2016) Size dependent classification of heat shock proteins: a mini-review. J Exerc Rehabil 12(4):255–259PubMedPubMedCentralCrossRefGoogle Scholar
  47. Jung TW, Lee SY, Hong HC, Choi HY, Yoo HJ, Baik SH, Choi KM (2014) AMPK activator-mediated inhibition of endoplasmic reticulum stress ameliorates carrageenan-induced insulin resistance through the suppression of selenoprotein P in HepG2 hepatocytes. Mol Cell Endocrinol 382:66–73PubMedCrossRefPubMedCentralGoogle Scholar
  48. Kayyali US, Donaldson C, Huang H, Abdelnour R, Hassoun PM (2001) Phosphorylation of xanthine dehydrogenase/oxidase in hypoxia. J Biol Chem 276:14359–14365PubMedCrossRefPubMedCentralGoogle Scholar
  49. Kim H, Moon SY, Kim JS, Baek CH, Kim M, Min JY, Lee SK (2015) Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis. Am J Physiol Ren Physiol 308:F226–F236CrossRefGoogle Scholar
  50. Koumenis C, Naczki C, Koritzinsky M, Rastani S, Diehl A, Sonenberg N, Koromilas A, Wouters BG (2002) Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2 alpha. Mol Cell Biol 22:7405–7416PubMedPubMedCentralCrossRefGoogle Scholar
  51. Kulisz A, Chen N, Chandel NS, Shao Z, Schumacker PT (2002) Mitochondrial ROS initiate phosphorylation of p38 MAP kinase during hypoxia in cardiomyocytes. Am J Physiol Lung Cell Mol Physiol 282:L1324–L1329PubMedCrossRefPubMedCentralGoogle Scholar
  52. Kumar GK, Klein JB (2004) Analysis of expression and posttranslational modification of proteins during hypoxia. J Appl Physiol 96:1178–1186PubMedCrossRefPubMedCentralGoogle Scholar
  53. Lee J, Hong SW, Park SE, Rhee EJ, Park CY, Oh KW, Park SW, Lee WY (2014) Exendin-4 attenuates endoplasmic reticulum stress through a SIRT1-dependent mechanism. Cell Stress Chap 19:649–656CrossRefGoogle Scholar
  54. Lewis NC, Bailey DM, Dumanoir GR, Messinger L, Lucas SJ, Cotter JD, Donnelly J, McEneny J, Young IS, Stembridge M, Burgess KR, Basnet AS, Ainslie PN (2014) Conduit artery structure and function in lowlanders and native highlanders: relationships with oxidative stress and role of sympatho excitation. J Physiol 592:1009–1024PubMedPubMedCentralCrossRefGoogle Scholar
  55. Li J, Wang Y, Wen X, Ma XN, Chen W, Huang F, Kou J, Qi LW, Liu B, Liu K (2015) Pharmacological activation of AMPK prevents Drp1-mediated mitochondrial fission and alleviates endoplasmic reticulum stress-associated endothelial dysfunction. J Mol Cell Cardiol 86:62–74PubMedCrossRefPubMedCentralGoogle Scholar
  56. Marhfour I, Lopez XM, Lefkaditis D, Salmon I, Allagnat F, Richardson SJ, Morgan NG, Eizirik DL (2012) Expression of endoplasmic reticulum stress markers in the islets of patients with type 1 diabetes. Diabetologia 55:2417–2420PubMedCrossRefPubMedCentralGoogle Scholar
  57. McGinnis G, Kliszczewiscz B, Barberio M, Ballmann C, Peters B, Slivka D, Dumke C, Cuddy J, Hailes W, Ruby B, Quindry J (2014) Acute hypoxia and exercise-induced blood oxidative stress. Int J Sport Nutr Exerc Metab 24:684–693PubMedCrossRefPubMedCentralGoogle Scholar
  58. Miller LE, McGinnis GR, Kliszczewicz B, Slivka D, Hailes W, Cuddy J, Dumke C, Ruby B, Quindry JC (2013) Blood oxidative-stress markers during a high-altitude trek. Int J Sport Nutr Exerc Metab 23:65–72PubMedCrossRefPubMedCentralGoogle Scholar
  59. Minet E, Mottet D, Michel G, Roland I, Raes M, Remacle J, Michielsa C (1999) Hypoxia-induced activation of HIF-1: role of HIF-1alpha-Hsp90 interaction. FEBS Lett 460:251–256PubMedCrossRefPubMedCentralGoogle Scholar
  60. Mishra OP, Ashraf QM, Delivoria-Papadopoulos M (2002) Phosphorylation of cAMP response element binding (CREB) protein during hypoxia in cerebral cortex of newborn piglets and the effect of nitric oxide synthase inhibition. Neuroscience 115:985–991PubMedCrossRefPubMedCentralGoogle Scholar
  61. Mohan RM, Golding S, Paterson DJ (2001) Intermittent hypoxia improves atrial tolerance to subsequent anoxia and reduces stress protein expression. Acta Physiol Scand 172:89–95PubMedCrossRefPubMedCentralGoogle Scholar
  62. Mohanraj P, Merola AJ, Wright VP, Clanton TL (1998) Antioxidants protect rat diaphragmatic muscle function under hypoxic conditions. J Appl Physiol 84:1960–1966PubMedCrossRefPubMedCentralGoogle Scholar
  63. Moore LG (2001) Human genetic adaptation to high altitude. High Alt Med Biol 2:257–279PubMedCrossRefPubMedCentralGoogle Scholar
  64. Nedic O, Rattan SI, Grune T, Trougakos IP (2013) Molecular effects of advanced glycation end products on cell signalling pathways, ageing and pathophysiology. Free Rad Res 47(1):28–38CrossRefGoogle Scholar
  65. Niforou K, Chemonidou C, Trougakos IP (2014) Molecular chaperones and proteostasis regulation during redox imbalance. Redox Biol 2:323–332PubMedPubMedCentralCrossRefGoogle Scholar
  66. Nishitoh H (2012) CHOP is a multifunctional transcription factor in the ER stress response. J Biochem 151:217–219PubMedCrossRefPubMedCentralGoogle Scholar
  67. Okada T, Yoshida H, Akazawa R, Negishi M, Mori K (2002) Distinct roles of activating transcription factor 6 (ATF6) and double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) in transcription during the mammalian unfolded protein response. Biochem J 366:585–594PubMedPubMedCentralCrossRefGoogle Scholar
  68. Panjwani NN, Popova L, Srivastava PK (2002) Heat shock proteins gp96 and hsp70 activate the release of nitric oxide by APCs. J Immunol 168:2997–3003PubMedPubMedCentralCrossRefGoogle Scholar
  69. Perez VI, Buffenstein R, Masamsetti V, Leonard S, Salmon AB, Mele J, Andziak B, Yang T, Edrey Y, Friguet B, Ward W, Richardson A, Chaudhuri A (2009) Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat. Proc Natl Acad Sci U S A 106:3059–3064PubMedPubMedCentralCrossRefGoogle Scholar
  70. Perreault K, Courchesne-Loyer A, Fortier M, Maltai M, Barsalani R, Riesco E, Dionne IJ (2016) Sixteen weeks of resistance training decrease plasma heat shock protein 72 (eHSP72) and increase muscle mass without affecting high sensitivity inflammatory markers’ levels in sarcopenic men. Aging Clin Exp Res 28:207–214PubMedCrossRefPubMedCentralGoogle Scholar
  71. Pockley AG, De Faire U, Kiessling R, Lemne C, Thulin T, Frostegard J (2002) Circulating heat shock protein and heat shock protein antibody levels in established hypertension. J Hypertens 20:1815–1820PubMedCrossRefPubMedCentralGoogle Scholar
  72. Pockley AG, Georgiades A, Thulin T, de Faire U, Frostegard J (2003) Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hypertension. Hypertension 42:235–238PubMedCrossRefPubMedCentralGoogle Scholar
  73. Powers ET, Morimoto RI, Dillin A, Kelly JW, Balch WE (2009) Biological and chemical approaches to diseases of proteostasis deficiency. Annu Rev Biochem 78:959–991PubMedCrossRefPubMedCentralGoogle Scholar
  74. Puri P, Mirshahi F, Cheung O, Natarajan R, Maher JW, Kellum JM, Sanyal AJ (2008) Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 134:568–576PubMedCrossRefPubMedCentralGoogle Scholar
  75. Qin L, Wang Z, Tao L, Wang Y (2010) ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy. Autophagy 6:239–247PubMedCrossRefPubMedCentralGoogle Scholar
  76. Radak Z, Lee K, Choi W, Sunoo S, Kizaki T, Ohishi S, Suzuki K, Taniguchi N, Ohno H, Asano K (1994) Oxidative stress induced by intermittent exposure at a simulated altitude of 4000 m decreases mitochondrial superoxide dismutase content in soleus muscle of rats. Eu J Appl Physiol 69:392–395CrossRefGoogle Scholar
  77. Rathor R, Sharma P, Suryakumar S, Ganju L (2015) A pharmacological investigation of Hippophae salicifolia (HS) and Hippophae rhamnoides turkestanica (HRT) against multiple stress (C-H-R): an experimental study using rat model. Cell Stress Chap 20:821–831CrossRefGoogle Scholar
  78. Roth DM, Balch WE (2011) Modeling general proteostasis: proteome balance in health and disease. Curr Opin Cell Biol 23:126–134PubMedCrossRefPubMedCentralGoogle Scholar
  79. Row BW, Goldbart A, Gozal E, Gozal D (2003) Spatial pre-training attenuates hippocampal impairments in rats exposed to intermittent hypoxia. Neurosci Lett 339:67–71PubMedCrossRefPubMedCentralGoogle Scholar
  80. Rutkowski DT, Hegde RS (2010) Regulation of basal cellular physiology by the homeostatic unfolded protein response. J Cell Biol 189:783–794PubMedPubMedCentralCrossRefGoogle Scholar
  81. Seimon TA, Nadolski MJ, Liao X, Magallon J, Nguyen M, Feric NT, Koschinsky ML, Harkewicz R, Witztum JL, Tsimikas S, Golenbock D, Moore KJ, Tabas I (2010) Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metab 12:467–482PubMedPubMedCentralCrossRefGoogle Scholar
  82. Sen S, Kundu BK, Wu HC, Hashmi SS, Guthrie P, Locke LW, Roy RJ, Matherne GP, Berr SS, Terwelp M, Scott B, Carranza S, Frazier OH, Glover DK, Dillmann WH, Gambello MJ, Entman ML, Taegtmeyer H (2013) Glucose regulation of load-induced mTOR signaling and ER stress in mammalian heart. J Am Heart Assoc 2:e004796PubMedPubMedCentralCrossRefGoogle Scholar
  83. Serrano J, Encinas JM, Salas E, Fernandez AP, Castro-Blanco S, Fernandez-Vizarra P, Bentura ML, Rodrigo J (2003) Hypobaric hypoxia modifies constitutive nitric oxide synthase activity and protein nitration in the rat cerebellum. Brain Res 976:109–119PubMedCrossRefPubMedCentralGoogle Scholar
  84. Sharma P, Jha AB, Dubey RS, Pessarakli M (2012) Reactive oxygen species, oxidative damage, and antioxidative defense mechanism in plants under stressful conditions. J Bot 2012:1–26CrossRefGoogle Scholar
  85. Shi Y, Vattem KM, Sood R, An J, Liang J (1998) Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol 18:7499–7509PubMedPubMedCentralCrossRefGoogle Scholar
  86. Shi Y, Baker JE, Zhang C, Tweddell JS, Su J, Pritchard KA Jr (2002) Chronic hypoxia increases endothelial nitric oxide synthase generation of nitric oxide by increasing heat shock protein 90 association and serine phosphorylation. Circ Res 91:300–306PubMedCrossRefPubMedCentralGoogle Scholar
  87. Sinha S, Ray US, Saha M, Singh SN, Tomar OS (2009a) Antioxidant and redox status after maximal aerobic exercise at high altitude in acclimatized lowlanders and native highlanders. Eur J Appl Physiol 106:807–814PubMedCrossRefPubMedCentralGoogle Scholar
  88. Sinha S, Ray US, Tomar OS, Singh SN (2009b) Different adaptation patterns of antioxidant system in natives and sojourners at high altitude. Resp Physiol Neurobiol 167:255–260CrossRefGoogle Scholar
  89. Sondermann H, Becker T, Mayhew M, Wieland F, Hartl FU (2000) Characterization of a receptor for heat shock protein 70 on macrophages and monocytes. Biol Chem 381:1165–1174PubMedCrossRefGoogle Scholar
  90. Srivastava P (2002) Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Annu Rev Immunol 20:395–425CrossRefGoogle Scholar
  91. Stadtman ER (1992) Protein oxidation and aging. Science 257:1220–1224PubMedCrossRefPubMedCentralGoogle Scholar
  92. Suryakumar G, Gupta A (2011) Medicinal and therapeutic potential of Sea buckthorn (Hippophae rhamnoides L.). J Ethnopharmacol 138(2):268–278PubMedCrossRefPubMedCentralGoogle Scholar
  93. Suzen E, Karademir B, Ozer NK (2015) Basic mechanisms in endoplasmic reticulum stress and relation to cardiovascular diseases. Free Rad Biol Med 78:30–41CrossRefGoogle Scholar
  94. Tang T, Arbiser JL, Brandt SJ (2002) Phosphorylation by mitogen activated protein kinase mediates the hypoxia-induced turnover of the TAL1/SCL transcription factor in endothelial cells. J Biol Chem 277:18365–18372PubMedCrossRefPubMedCentralGoogle Scholar
  95. Terry DF, McCormick M, Andersen S, Pennington J, Schoenhofen E, Palaima E, Bausero M, Ogawa K, Perls TT, Asea A (2004) Cardiovascular disease delay in centenarian offspring: role of heat shock proteins. Ann N Y Acad Sci 1019:502–505PubMedPubMedCentralCrossRefGoogle Scholar
  96. Tersey SA, Nishiki Y, Templin AT, Cabrera SM, Stull ND, Colvin SC, Evans-Molina C, Rickus JL, Maier B, Mirmira RG (2012) Islet β-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model. Diabetes 61:818–827PubMedPubMedCentralCrossRefGoogle Scholar
  97. Trougakos IP, Sesti F, Tsakiri E, Gorgoulis VG (2013) Non-enzymatic posttranslational protein modifications and proteostasis network deregulation in carcinogenesis. J Proteome 92:274–298CrossRefGoogle Scholar
  98. Usui M, Yamaguchi S, Tanji Y, Tominaga R, Ishigaki Y, Fukumoto M, Katagiri H, Mori K, Oka Y, Ishihara H (2012) Atf6α-null mice are glucose intolerant due to pancreatic β-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance. Metabolism 61:1118–1128PubMedCrossRefPubMedCentralGoogle Scholar
  99. Vabulas RM, Ahmad-Nejad P, Ghose S, Kirschning CJ, Issels RD, Wagner H (2002) HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem 277:15107–15112CrossRefPubMedPubMedCentralGoogle Scholar
  100. Verma G, Datta M (2012) The critical role of JNK in the ER-mitochondrial crosstalk during apoptotic cell death. J Cell Physiol 227:1791–1795PubMedCrossRefPubMedCentralGoogle Scholar
  101. Weinberg JM, Venkatachalam MA, Roeser NF, Senter RA, Nissim I (2001) Energetic determinants of tyrosine phosphorylation of focal adhesion proteins during hypoxia/reoxygenation of kidney proximal tubules. Am J Pathol 158:2153–2164PubMedPubMedCentralCrossRefGoogle Scholar
  102. Witko-Sarsat V, Frielander M, Capeille’re-Blandin C, Nguyen-Khoa T, Nguyen AT, Zingraff J, Jungers P, Descamps-Latscha B (1996) Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int 49:1304–1313PubMedCrossRefPubMedCentralGoogle Scholar
  103. Witko-Sarsat V, Frielander M, Nguyen-Khoa T, Capeillere-Blandin C, Nguyen AT, Canteloup S, Dayer JM, Jungers P, Drüeke T, Descamps-Latscha B (1998) Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure. J Immunol 161:2524–2532PubMedPubMedCentralGoogle Scholar
  104. Wright BH, Corton JM, El-Nahas AM, Wood RF, Pockley AG (2000) Elevated levels of circulating heat shock protein 70 (Hsp70) in peripheral and renal vascular disease. Heart Vessel 15:18–22CrossRefGoogle Scholar
  105. Xin X, Dang H, Zhao X, Wang H (2017) Effects of hypobaric hypoxia on rat retina and protective response of resveratrol to the stress. Int J Med Sci 14(10):943–950PubMedPubMedCentralCrossRefGoogle Scholar
  106. Yamane S, Hamamoto Y, Harashima S, Harada N, Hamasaki A, Toyoda K, Fujita K, Joo E, Seino Y, Inagaki N (2011) GLP-1 receptor agonist attenuates endoplasmic reticulum stress-mediated β-cell damage in Akita mice. J Diabet Investig 2:104–110CrossRefGoogle Scholar
  107. Yin J, Gu L, Wang Y, Fan N, Ma Y, Peng Y (2015) Rapamycin improves palmitate-induced ER stress/NF κB pathways associated with stimulating autophagy in adipocytes. Mediat Inflamm 2015:1–12Google Scholar
  108. Yorimitsu T, Klionsky DJ (2007) Endoplasmic reticulum stress: a new pathway to induce autophagy. Autophagy 3:160–162PubMedCrossRefPubMedCentralGoogle Scholar
  109. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107:881–891PubMedPubMedCentralCrossRefGoogle Scholar
  110. Younce CW, Burmeister MA, Ayala JE (2013) Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a. Am J Physiol Cell Physiol 304:C508–C518PubMedCrossRefPubMedCentralGoogle Scholar
  111. Yusta B, Baggio LL, Estall JL, Koehler JA, Holland DP, Li H, Pipeleers D, Ling Z, Drucker DJ (2006) GLP-1 receptor activation improves β cell function and survival following induction of endoplasmic reticulum stress. Cell Metab 4:391–406PubMedCrossRefPubMedCentralGoogle Scholar
  112. Zhang K, Kaufman RJ (2008) From endoplasmic-reticulum stress to the inflammatory response. Nature 454:455–462PubMedPubMedCentralCrossRefGoogle Scholar
  113. Zhang K, Wang S, Malhotra J, Hassler JR, Back SH, Wang G, Chang L, Xu W, Miao H, Leonardi R, Chen YE, Jackowski S, Kaufman RJ (2011) The unfolded protein response transducer IRE1α prevents ER stress-induced hepatic steatosis. EMBO J 30:1357–1375PubMedPubMedCentralCrossRefGoogle Scholar
  114. Zhang J, Li Y, Jiang S, Yu H, An W (2014) Enhanced endoplasmic reticulum SERCA activity by overexpression of hepatic stimulator substance gene prevents hepatic cells from ER stress-induced apoptosis. Am J Physiol Cell Physiol 306:C279–C290PubMedCrossRefPubMedCentralGoogle Scholar
  115. Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT (1998) CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 12:982–995PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Cellular Biochemistry DivisionDefence Institute of Physiology and Allied SciencesDelhiIndia

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