Advertisement

The Journal of Physiological Sciences

, Volume 68, Issue 1, pp 55–67 | Cite as

Cardioprotection of exercise preconditioning involving heat shock protein 70 and concurrent autophagy: a potential chaperone-assisted selective macroautophagy effect

  • Yang Yuan
  • Shan-Shan PanEmail author
  • Yu-Jun Shen
Original Paper
First Online:

Abstract

It has been confirmed that exercise preconditioning (EP) has a protective effect on acute cardiovascular stress. However, how Hsp70 participates in EP-induced cardioprotection is unknown. EP may involve Hsp70 to repair unfolded proteins or may also stabilize the function of the endoplasmic reticulum via Hsp70-related autophagy to work on a protective formation. Our EP protocol involves four periods of 10 min running with 10 min recovery intervals. We added a period of exhaustive running to test this protective effect, using histology and molecular biotechnology methods to detect related markers. EP provided cardioprotection at its early and late phases against exhaustive exercise-induced ischemic myocardial injury. Results showed that Hsp70 co-chaperone protein BAG3, ubiquitin adaptor p62 and critical autophagy protein LC3 were significantly upregulated at the early phase. Meanwhile, Hsp70, Hsp70/BAG3 co-localization extent, LC31 and LC3II were significantly upregulated at the late phase. Hsp70 mRNA levels and LC3II/I ratios were also consistent with the extent of myocardial injury following exhaustive exercise. Hsp70 increase was delayed relative to BAG3 and p62 after EP, indicating a pre-synthesized phenomenon of BAG3 and p62 for chaperone-assisted selective autophagy (CASA). The decreased Hsp70, BAG3 and p62 levels and increased Hsp70/BAG3 co-localization extent and LC3 levels induced by exhaustive exercise after EP suggest that EP-induced cardioprotection might associate with CASA. Hsp70 has a cardioprotective role and has a closer link with CASA in LEP. Additionally, EP may not cause exhaustion-dependent excessive autophagy regulation. Collectively, during early and late EP, CASA potentially plays different roles in cardioprotection.

Keywords

Exercise preconditioning Cardioprotection Molecular chaperone Macroautophagy Hsp70 

Abbreviations

EP

Exercise preconditioning

EEP

Early exercise preconditioning

LEP

Late exercise preconditioning

Hsp70

Heat shock protein 70

BAG3

Bcl-2 associated athanogene 3

LC3

Microtubule-associated protein 1A/1B light chain 3

UPR

Unfolded protein response

ERS

Endoplasmic reticulum stress

UPS

Ubiquitin-proteasome system

CMA

Chaperone-mediated autophagy

Hsc70

70 kDa heat shock cognate protein

CASA

Chaperone-assisted selective autophagy

EE

Exhaustive exercise

cTnI

Cardiac troponin I

HSF

Heat shock factor

This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (no. 31471136).

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

References

  1. 1.
    Hoshimoto-Iwamoto M, Koike A, Nagayama O, Tajima A, Suzuki T, Uejima T, Sawada H, Aizawa T (2009) Prognostic value of end-tidal CO2 pressure during exercise in patients with left ventricular dysfunction. J Physiol Sci 59(1):49–55PubMedCrossRefGoogle Scholar
  2. 2.
    Jimenez SK, Jassal DS, Kardami E, Cattini PA (2011) A single bout of exercise promotes sustained left ventricular function improvement after isoproterenol-induced injury in mice. J Physiol Sci 61(4):331–336PubMedCrossRefGoogle Scholar
  3. 3.
    Hao Z, Pan SS, Shen YJ, Ge J (2014) Exercise preconditioning-induced early and late phase of cardioprotection is associated with protein kinase C epsilon translocation. Circ J 78(7):1636–1645PubMedCrossRefGoogle Scholar
  4. 4.
    Marongiu E, Crisafulli A (2014) Cardioprotection acquired through exercise: the role of ischemic preconditioning. Curr Cardiol Rev 10(4):336–348PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Shen YJ, Pan SS, Ge J, Hao Z (2012) Exercise preconditioning provides early cardioprotection against exhaustive exercise in rats: potential involvement of protein kinase C delta translocation. Mol Cell Biochem 368(1–2):89–102PubMedCrossRefGoogle Scholar
  6. 6.
    Lu J, Pan SS (2016) Elevated C-type natriuretic peptide elicits exercise preconditioning-induced cardioprotection against myocardial injury probably via the up-regulation of NPR-B. J Physiol Sci. doi: 10.1007/s12576-016-0477-9 PubMedCrossRefGoogle Scholar
  7. 7.
    Domenech R, Macho P, Schwarze H, Sánchez G (2002) Exercise induces early and late myocardial preconditioning in dogs. Cardiovasc Res 55(3):561–566PubMedCrossRefGoogle Scholar
  8. 8.
    Parra VM, Macho P, Sánchez G, Donoso P, Domenech RJ (2015) Exercise preconditioning of myocardial infarct size in dogs is triggered by calcium. J Cardiovasc Pharmacol 65(3):276–281PubMedCrossRefGoogle Scholar
  9. 9.
    Yin C, Salloum FN, Kukreja RC (2009) A novel role of microRNA in late preconditioning: upregulation of endothelial nitric oxide synthase and heat shock protein 70. Circ Res 104(5):572–575PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Hwang JK, Kim JM, Kim YK, Kim SD, Park SC, Kim JI, Nam HW, Kim J, Moon IS (2013) The early protective effect of glutamine pretreatment and ischemia preconditioning in renal ischemia-reperfusion injury of rat. Transpl Proc 45(9):3203–3208CrossRefGoogle Scholar
  11. 11.
    Madden LA, Sandstrom ME, Lovell RJ, McNaughton L (2008) Inducible heat shock protein 70 and its role in preconditioning and exercise. Amino Acids 34(4):511–516PubMedCrossRefGoogle Scholar
  12. 12.
    Sheng R, Liu XQ, Zhang LS, Gao B, Han R, Wu YQ, Zhang XY, Qin ZH (2012) Autophagy regulates endoplasmic reticulum stress in ischemic preconditioning. Autophagy 8(3):310–325PubMedCrossRefGoogle Scholar
  13. 13.
    Melling CW, Thorp DB, Milne KJ, Noble EG (2009) Myocardial Hsp70 phosphorylation and PKC-mediated cardioprotection following exercise. Cell Stress Chaperones 14(2):141–150PubMedCrossRefGoogle Scholar
  14. 14.
    Powers SK, Demirel HA, Vincent HK, Coombes JS, Naito H, Hamilton KL, Shanely RA, Jessup J (1998) Exercise training improves myocardial tolerance to in vivo ischemia-reperfusion in the rat. Am J Physiol 275(5 Pt 2):R1468–R1477PubMedGoogle Scholar
  15. 15.
    Xu T, Zhang B, Yang F, Cai C, Wang G, Han Q, Zou L (2015) HSF1 and NF-kappaB p65 participate in the process of exercise preconditioning attenuating pressure overload-induced pathological cardiac hypertrophy. Biochem Biophys Res Commun 460(3):622–627PubMedCrossRefGoogle Scholar
  16. 16.
    Lee BJ, Emery-Sinclair EL, Mackenzie RW, Hussain A, Taylor L, James RS, Thake CD (2014) The impact of submaximal exercise during heat and/or hypoxia on the cardiovascular and monocyte HSP72 responses to subsequent (post 24 h) exercise in hypoxia. Extreme Physiol Med 3:15CrossRefGoogle Scholar
  17. 17.
    Willis MS, Min JN, Wang S, McDonough H, Lockyer P, Wadosky KM, Patterson C (2013) Carboxyl terminus of Hsp70-interacting protein (CHIP) is required to modulate cardiac hypertrophy and attenuate autophagy during exercise. Cell Biochem Funct 31(8):724–735PubMedCrossRefGoogle Scholar
  18. 18.
    Li B, Tian J, Sun Y, Xu TR, Chi RF, Zhang XL, Hu XL, Zhang YA, Qin FZ, Zhang WF (2015) Activation of NADPH oxidase mediates increased endoplasmic reticulum stress and left ventricular remodeling after myocardial infarction in rabbits. Biochim Biophys Acta 1852(5):805–815. doi: 10.1016/j.bbadis.2015.01.010 PubMedCrossRefGoogle Scholar
  19. 19.
    Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403(6765):98–103PubMedCrossRefGoogle Scholar
  20. 20.
    Lamark T, Johansen T (2012) Aggrephagy: selective disposal of protein aggregates by macroautophagy. Int J Cell Biol 2012:736905PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Qi L, Zhang XD, Wu JC, Lin F, Wang J, DiFiglia M, Qin ZH (2012) The role of chaperone-mediated autophagy in huntingtin degradation. PLoS One 7(10):e46834 doi:46810.41371/journal.pone.0046834 PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Klionsky DJ, Codogno P (2013) The mechanism and physiological function of macroautophagy. J Innate Immun 5(5):427–433. doi: 10.1159/000351979 PubMedCrossRefGoogle Scholar
  23. 23.
    Gurusamy N, Das DK (2009) Autophagy, redox signaling, and ventricular remodeling. Antioxid Redox Signal 11(8):1975–1988PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Omatsu-Kanbe M, Matsuura H (2013) Ischemic survival and constitutively active autophagy in self-beating atypically-shaped cardiomyocytes (ACMs): characterization of a new subpopulation of heart cells. J Physiol Sci 63(1):17–29PubMedCrossRefGoogle Scholar
  25. 25.
    Jarrett CL, D’Lugos AC, Mahmood TN, Gonzales RJ, Hale TM, Carroll CC, Dickinson JM, Angadi SS (2016) Effect of high intensity exercise preconditioning and training on antioxidant enzymes in cardiomyocytes during doxorubicin treatment. FASEB J 30(1 Supplement):lb601–lb601Google Scholar
  26. 26.
    Wang L, Deng W, Yuan Q, Yang H (2015) Exercise preconditioning reduces ischemia reperfusion-induced focal cerebral infarct volume through up-regulating the expression of HIF-1alpha. Pak J Pharm Sci 28(2 Suppl):791–798PubMedGoogle Scholar
  27. 27.
    Huang C, Yitzhaki S, Perry CN, Liu W, Giricz Z, Mentzer RM Jr, Gottlieb RA (2010) Autophagy induced by ischemic preconditioning is essential for cardioprotection. J Cardiovasc Transl Res 3(4):365–373PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, An Z, Loh J, Fisher J, Sun Q (2012) Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481(7382):511–515PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Lee J, Park S, Kim WK (2013) Exercise preconditioning reduces acute ischemic renal injury in Hsp70.1 knockout mouse. Histol Histopathol 28(9):1223–1233PubMedGoogle Scholar
  30. 30.
    Gamerdinger M, Kaya AM, Wolfrum U, Clement AM, Behl C (2011) BAG3 mediates chaperone-based aggresome-targeting and selective autophagy of misfolded proteins. EMBO Rep 12(2):149–156PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Ulbricht A, Hohfeld J (2013) Tension-induced autophagy: may the chaperone be with you. Autophagy 9(6):920–922PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    De Meyer GR, Martinet W (2009) Autophagy in the cardiovascular system. Biochim Biophys Acta 1793(9):1485–1495PubMedCrossRefGoogle Scholar
  33. 33.
    Shen YJ, Pan SS, Zhuang T, Wang FJ (2011) Exercise preconditioning initiates late cardioprotection against isoproterenol-induced myocardial injury in rats independent of protein kinase C. J Physiol Sci 61(1):13–21PubMedCrossRefGoogle Scholar
  34. 34.
    Lennon SL, Quindry JC, French JP, Kim S, Mehta JL, Powers SK (2004) Exercise and myocardial tolerance to ischaemia-reperfusion. Acta Physiol Scand 182(2):161–169PubMedCrossRefGoogle Scholar
  35. 35.
    Dunn KW, Kamocka MM, McDonald JH (2011) A practical guide to evaluating colocalization in biological microscopy. Am J Physiol Cell Physiol 300(4):C723–C742PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Dokladny K, Myers OB, Moseley PL (2015) Heat shock response and autophagy-cooperation and control. Autophagy 11(2):200–213PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Melling CW, Thorp DB, Milne KJ, Krause MP, Noble EG (2007) Exercise-mediated regulation of Hsp70 expression following aerobic exercise training. Am J Physiol Heart Circ Physiol 293(6):H3692–H3698PubMedCrossRefGoogle Scholar
  38. 38.
    Hung CH, Chang NC, Cheng BC, Lin MT (2005) Progressive exercise preconditioning protects against circulatory shock during experimental heatstroke. Shock 23(5):426–433PubMedCrossRefGoogle Scholar
  39. 39.
    Chen H, Adam A, Cheng Y, Tang S, Hartung J, Bao E (2015) Localization and expression of heat shock protein 70 with rat myocardial cell damage induced by heat stress in vitro and in vivo. Mol Med Rep 11(3):2276–2284PubMedCrossRefGoogle Scholar
  40. 40.
    Ulbricht A, Gehlert S, Leciejewski B, Schiffer T, Bloch W, Hohfeld J (2015) Induction and adaptation of chaperone-assisted selective autophagy CASA in response to resistance exercise in human skeletal muscle. Autophagy 11(3):538–546PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Periard JD, Ruell PA, Thompson MW, Caillaud C (2015) Moderate- and high-intensity exhaustive exercise in the heat induce a similar increase in monocyte Hsp72. Cell Stress Chaperones 20(6):1037–1042PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Doong H, Rizzo K, Fang S, Kulpa V, Weissman AM, Kohn EC (2003) CAIR-1/BAG-3 abrogates heat shock protein-70 chaperone complex-mediated protein degradation: accumulation of poly-ubiquitinated Hsp90 client proteins. J Biol Chem 278(31):28490–28500PubMedCrossRefGoogle Scholar
  43. 43.
    Mozaffari MS, Liu JY, Abebe W, Baban B (2013) Mechanisms of load dependency of myocardial ischemia reperfusion injury. Am J Cardiovasc Dis 3(4):180PubMedPubMedCentralGoogle Scholar
  44. 44.
    Hishiya A, Kitazawa T, Takayama S (2010) BAG3 and Hsc70 interact with actin capping protein CapZ to maintain myofibrillar integrity under mechanical stress. Circ Res 107(10):1220–1231PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Gibson NM, Greufe SE, Hydock DS, Hayward R (2013) Doxorubicin-induced vascular dysfunction and its attenuation by exercise preconditioning. J Cardiovasc Pharmacol 62(4):355–360PubMedCrossRefGoogle Scholar
  46. 46.
    Bloemberg D, McDonald E, Dulay D, Quadrilatero J (2014) Autophagy is altered in skeletal and cardiac muscle of spontaneously hypertensive rats. Acta Physiologica (Oxford, England) 210(2):381–391CrossRefGoogle Scholar
  47. 47.
    Zheng Q, Su H, Ranek MJ, Wang X (2011) Autophagy and p62 in cardiac proteinopathy. Circ Res 109(3):296–308PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Park S, Choi SG, Yoo SM, Son JH, Jung YK (2014) Choline dehydrogenase interacts with SQSTM1/p62 to recruit LC3 and stimulate mitophagy. Autophagy 10(11):1906–1920PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Jiang P, Mizushima N (2015) LC3- and p62-based biochemical methods for the analysis of autophagy progression in mammalian cells. Methods 75:13–18. doi: 10.1016/j.ymeth.2014.11.021 PubMedCrossRefGoogle Scholar
  50. 50.
    Hariharan N, Maejima Y, Nakae J, Paik J, Depinho RA, Sadoshima J (2010) Deacetylation of FoxO by sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes. Circ Res 107(12):1470–1482PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Paula-Gomes S, Goncalves DA, Baviera AM, Zanon NM, Navegantes LC, Kettelhut IC (2013) Insulin suppresses atrophy- and autophagy-related genes in heart tissue and cardiomyocytes through AKT/FOXO signaling. Horm Metab Res 45(12):849–855PubMedCrossRefGoogle Scholar
  52. 52.
    Dokladny K, Zuhl MN, Mandell M, Bhattacharya D, Schneider S, Deretic V, Moseley PL (2013) Regulatory coordination between two major intracellular homeostatic systems: heat shock response and autophagy. J Biol Chem 288(21):14959–14972PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Overvatn A, Bjorkoy G, Johansen T (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282(33):24131–24145. doi: 10.1074/jbc.M702824200 PubMedCrossRefGoogle Scholar
  54. 54.
    Perez-Perez ME, Zaffagnini M, Marchand CH, Crespo JL, Lemaire SD (2014) The yeast autophagy protease Atg4 is regulated by thioredoxin. Autophagy 10(11):1953–1964PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Sharifi MN, Mowers EE, Drake LE, Macleod KF (2015) Measuring autophagy in stressed cells. Methods Mol Biol 1292:129–150PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Gurusamy N, Das DK (2009) Is autophagy a double-edged sword for the heart? Acta Physiol Hung 96(3):267–276. doi: 10.1556/APhysiol.96.2009.3.2 PubMedCrossRefGoogle Scholar
  57. 57.
    Qin L, Wang Z, Tao L, Wang Y (2010) ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy. Autophagy 6(2):239–247PubMedCrossRefGoogle Scholar
  58. 58.
    Smuder AJ, Kavazis AN, Min K, Powers SK (2013) Doxorubicin-induced markers of myocardial autophagic signaling in sedentary and exercise trained animals. J Appl Physiol (Bethesda, Md: 1985) 115(2):176–185CrossRefGoogle Scholar

Copyright information

© The Physiological Society of Japan and Springer Japan 2016

Authors and Affiliations

  1. 1.School of KinesiologyShanghai University of SportShanghaiChina

Personalised recommendations

Cite article

Buy options