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Cardioprotection by ischemic postconditioning is abolished in depressed rats: role of Akt and signal transducer and activator of transcription-3

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Abstract

Ischemic postconditioning (IPC) represents one of the most effective cardioprotective strategies against myocardial ischemia/reperfusion. Depression is commonly present in patients with coronary heart disease. However, whether depression interferes with the cardioprotection of IPC during myocardial ischemia/reperfusion and their underlying mechanisms remain largely unknown. Isolated hearts from chronic mild stress induced-depressed rats and non-depressed rats were subjected to 30 min of regional ischemia followed by 120 min of reperfusion in the presence or absence of IPC (consisting of 6 cycles of 10 s of reperfusion and 10 s of ischemia immediately after the sustained ischemia). Myocardial infarct size, creatine kinase (CK) and cardiac troponin T (cTnT) release, cardiac function and phosphorylated AKT and signal transducer and activator of transcription-3 (STAT-3) were measured. IPC significantly prevented the hearts from myocardial ischemia/reperfusion injury by decreasing infarct size, and CK and cTnT release in coronary effluent, and improving cardiac functional recovery in non-depressed rats. However, these cardioprotective effects of IPC were not observed in depressed rats. In addition, IPC had no effects on the phosphorylation of AKT and STAT-3 at reperfusion in depressed hearts, although it markedly increased the phosphorylation of AKT and STAT-3 at reperfusion in non-depressed hearts. In conclusion, these data indicate that cardioprotection by IPC is abolished during myocardial ischemia/reperfusion in depressed rats, and the underlying mechanisms are probably related to the impaired activation of AKT and STAT-3 at reperfusion.

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References

  1. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285:H579–H588

    CAS  PubMed  Google Scholar 

  2. Yellon DM, Hausenloy DJ (2003) Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev 83:1113–1151

    CAS  PubMed  Google Scholar 

  3. Yellon DM, Hausenloy DJ (2005) Realizing the clinical potential of ischemic preconditioning and postconditioning. Nat Clin Pract 2:568–575

    Google Scholar 

  4. Hausenloy DJ, Yellon DM (2009) Preconditioning and postconditioning: underlying mechanisms and clinical application. Atherosclerosis 204:334–341

    Article  CAS  PubMed  Google Scholar 

  5. Yellon DM, Hausenloy DJ (2007) Myocardial reperfusion injury. N Engl J Med 357:1121–1135

    Article  CAS  PubMed  Google Scholar 

  6. Hausenloy DJ, Yellon DM (2006) Survival kinases in ischemic preconditioning and postconditioning. Cardiovasc Res 70:240–253

    Article  CAS  PubMed  Google Scholar 

  7. Tsang A, Hausenloy DJ, Mocanu MM, Yellon DM (2004) Postconditioning: a form of “modified reperfusion” protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway. Circ Res 95:230–232

    Article  CAS  PubMed  Google Scholar 

  8. Lacerda L, Somers S, Opie LH, Lecour S (2009) Ischaemic postconditioning protects against reperfusion injury via the SAFE pathway. Cardiovasc Res 84:201–208

    Article  CAS  PubMed  Google Scholar 

  9. Boengler K, Buechert A, Heinen Y, Roeskes C, Hilfiker-Kleiner D, Heusch G, Schulz R (2008) Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice. Circ Res 102:131–135

    Article  CAS  PubMed  Google Scholar 

  10. Wagner C, Tillack D, Simonis G, Strasser RH, Weinbrenner C (2010) Ischemic post-conditioning reduces infarct size of the in vivo rat heart: role of PI3-K, mTOR, GSK-3beta, and apoptosis. Mol Cell Biochem 339:135–147

    Article  CAS  PubMed  Google Scholar 

  11. Heusch G, Boengler K, Schulz R (2008) Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation 118:1915–1919

    Article  PubMed  Google Scholar 

  12. Boengler K, Hilfiker-Kleiner D, Drexler H, Heusch G, Schulz R (2008) The myocardial JAK/STAT pathway: from protection to failure. Pharmacol Ther 120:172–185

    Article  CAS  PubMed  Google Scholar 

  13. Skyschally A, Schulz R, Heusch G (2008) Pathophysiology of myocardial infarction: protection by ischemic pre- and postconditioning. Herz 33:88–100

    Article  PubMed  Google Scholar 

  14. Ovize M, Baxter GF, Di Lisa F, Ferdinandy P, Garcia-Dorado D, Hausenloy DJ, Heusch G, Vinten-Johansen J, Yellon DM, Schulz R (2010) Postconditioning and protection from reperfusion injury: where do we stand? Position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res 87:406–423

    Article  CAS  PubMed  Google Scholar 

  15. Hilfiker-Kleiner D, Hilfiker A, Fuchs M, Kaminski K, Schaefer A, Schieffer B, Hillmer A, Schmiedl A, Ding Z, Podewski E, Podewski E, Poli V, Schneider MD, Schulz R, Park JK, Wollert KC, Drexler H (2004) Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury. Circ Res 95:187–195

    Article  CAS  PubMed  Google Scholar 

  16. Balakumar P, Rohilla A, Singh M, Anand-Srivastava MB (2008) Pre-conditioning and postconditioning to limit ischemia-reperfusion-induced myocardial injury: what could be the next footstep? Pharmacol Res 57:403–412

    Article  PubMed  Google Scholar 

  17. Ferdinandy P, Schulz R, Baxter GF (2007) Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. Pharmacol Rev 59:418–458

    Article  CAS  PubMed  Google Scholar 

  18. Frasure-Smith N, Lesperance F (2010) Depression and cardiac risk: present status and future directions. Heart 96:173–176

    Article  PubMed  Google Scholar 

  19. Rozanski A, Blumenthal JA, Kaplan J (1999) Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation 99:2192–2217

    CAS  PubMed  Google Scholar 

  20. Lichtman JH, Bigger JT, Blumenthal JA, Frasure-Smith N, Kaufmann PG, Lesperance F, Mark DB, Sheps DS, Taylor CB, Froelicher ES (2008) Depression and coronary heart disease: recommendations for screening, referral, and treatment. Circulation 118:1768–1775

    Article  PubMed  Google Scholar 

  21. Willner P, Muscat R, Papp M (1992) Chronic mild stress-induced anhedonia: a realistic animal model of depression. Neurosci Biobehav Rev 16:525–534

    Article  CAS  PubMed  Google Scholar 

  22. Kocsis GF, Pipis J, Fekete V, Kovacs-Simon A, Odendaal L, Molnar E, Giricz Z, Janáky T, van Rooyen J, Csont T, Ferdinandy P (2008) Lovastatin interferes with the infarct size-limiting effect of ischemic preconditioning and postconditioning in rat hearts. Am J Physiol Heart Circ Physiol 294:H2406–H2409

    Article  CAS  PubMed  Google Scholar 

  23. Jang Y, Xi J, Wang H, Mueller RA, Norfleet EA, Xu Z (2008) Postconditioning prevents reperfusion injury by activating delta-opioid receptors. Anesthesiology 108:243–250

    Article  CAS  PubMed  Google Scholar 

  24. Papp M, Moryl E, Willner P (1996) Pharmacological validation of the chronic mild stress model of depression. Eur J Pharmacol 296:129–136

    Article  CAS  PubMed  Google Scholar 

  25. Grippo AJ, Johnson AK (2009) Stress, depression, and cardiovascular dysregulation: a review of neurobiological mechanisms and the integration of research from preclinical disease models. Stress 12:1–21

    Article  CAS  PubMed  Google Scholar 

  26. Willner P (1997) Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology 134:1319–1329

    Google Scholar 

  27. World Health Organization (2008) The global burden of disease: 2004 update. World health Organization, Geneva

    Google Scholar 

  28. Thombs BD, Bass EB, Ford DE, Stewart KJ, Tsilidis KK, Patel U, Fauerbach JA, Bush DE, Ziegelstein RC (2006) Prevalence of depression in survivors of acute myocardial infarction. J Gen Intern Med 21:30–38

    Article  PubMed  Google Scholar 

  29. Musselman DL, Evans DL, Nemeroff CB (1998) The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. Arch Gen Psychiatry 55:580–592

    Article  CAS  PubMed  Google Scholar 

  30. Blazer DG, Kessler RC, McGonagle KA, Swartz MS (1994) The prevalence and distribution of major depression in a national community sample: the national co-morbidity survey. Am J Psychiatry 151:979–986

    CAS  PubMed  Google Scholar 

  31. Hans M, Carney RM, Freedland KE, Skala J (1996) Depression in patients with coronary heart disease: a 12-month follow-up. Gen Hosp Psychiatry 18:61–65

    Article  Google Scholar 

  32. Solskov L, Lofgren B, Pold R, Kristiansen SB, Nielsen TT, Overstreet DH, Schmitz O, Botker HE, Lund S, Wegener G (2010) Evaluation of the relationship between hyperinsulinaemia and myocardial ischaemia/reperfusion injury in a rat model of depression. Clin Sci (Lond) 118:259–267

    Article  Google Scholar 

  33. Bouhidel O, Pons S, Souktani R, Zini R, Berdeaux A, Ghaleh B (2008) Myocardial ischemic postconditioning against ischemia-reperfusion is impaired in ob/ob mice. Am J Physiol Heart Circ Physiol 295:H1580–H1586

    Article  CAS  PubMed  Google Scholar 

  34. Tsang A, Hausenloy DJ, Mocanu MM, Carr RD, Yellon DM (2005) Preconditioning the diabetic heart: the importance of Akt phosphorylation. Diabetes 54:2360–2364

    Article  CAS  PubMed  Google Scholar 

  35. Butler KL, Huffman LC, Koch SE, Hahn HS, Gwathmey JK (2006) STAT-3 activation is necessary for ischemic preconditioning in hypertrophied myocardium. Am J Physiol Heart Circ Physiol 291:H797–H803

    Article  CAS  PubMed  Google Scholar 

  36. Yadav HN, Singh M, Sharma PL (2010) Involvement of GSK-3beta in attenuation of the cardioprotective effect of ischemic preconditioning in diabetic rat heart. Mol Cell Biochem. doi:10.1007/s11010-010-0500-z

  37. Feng P, Guan Z, Yang X, Fang J (2003) Impairments of ERK signal transduction in the brain in a rat model of depression induced by neonatal exposure of clomipramine. Brain Res 991:195–205

    Article  CAS  PubMed  Google Scholar 

  38. Krishnan V, Han MH, Mazei-Robison M, Iniguez SD, Ables JL, Vialou V, Berton O, Ghose S, Covington HE 3rd, Wiley MD, Henderson RP, Neve RL, Eisch AJ, Tamminga CA, Russo SJ, Bolaños CA, Nestler EJ (2008) AKT signaling within the ventral tegmental area regulates cellular and behavioral responses to stressful stimuli. Biol Psychiatry 64:691–700

    Article  CAS  PubMed  Google Scholar 

  39. Coyle JT, Duman RS (2003) Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron 38:157–160

    Article  CAS  PubMed  Google Scholar 

  40. Grippo AJ, Francis J, Beltz TG, Felder RB, Johnson AK (2005) Neuroendocrine and cytokine profile of chronic mild stress-induced anhedonia. Physiol Behav 84:697–706

    Article  CAS  PubMed  Google Scholar 

  41. Shelton RC (2007) The molecular neurobiology of depression. Psychiatr Clin North Am 30:1–11

    Article  PubMed  Google Scholar 

  42. Lee S, Chanoit G, McIntosh R, Zvara DA, Xu Z (2009) Molecular mechanism underlying Akt activation in zinc-induced cardioprotection. Am J Physiol Heart Circ Physiol 297:H569–H575

    Article  CAS  PubMed  Google Scholar 

  43. Ruan H, Li J, Ren S, Gao J, Li G, Kim R, Wu H, Wang Y (2009) Inducible and cardiac specific PTEN inactivation protects ischemia/reperfusion injury. J Mol Cell Cardiol 46:193–200

    Article  CAS  PubMed  Google Scholar 

  44. Xie P, Guo S, Fan Y, Zhang H, Gu D, Li H (2009) Atrogin-1/MAFbx enhances simulated ischemia/reperfusion-induced apoptosis in cardiomyocytes through degradation of MAPK phosphatase-1 and sustained JNK activation. J Biol Chem 284:5488–5496

    Article  CAS  PubMed  Google Scholar 

  45. Miyamoto S, Purcell NH, Smith JM, Gao T, Whittaker R, Huang K, Castillo R, Glembotski CC, Sussman MA, Newton AC, Heller Brown J (2010) PHLPP-1 negatively regulates Akt activity and survival in the heart. Circ Res. doi:10.1161/CIRCRESAHA.109.215020

  46. Keyes KT, Xu J, Long B, Zhang C, Hu Z, Ye Y (2010) Pharmacological inhibition of PTEN limits myocardial infarct size and improves left ventricular function postinfarction. Am J Physiol Heart Circ Physiol 298:H1198–H1208

    Article  CAS  PubMed  Google Scholar 

  47. Przyklenk K, Maynard M, Darling CE, Whittaker P (2008) Aging mouse hearts are refractory to infarct size reduction with post-conditioning. J Am Coll Cardiol 51:1393–1398

    Article  PubMed  Google Scholar 

  48. Lin YH, Liu AH, Xu Y, Tie L, Yu HM, Li XJ (2005) Effect of chronic unpredictable mild stress on brain-pancreas relative protein in rat brain and pancreas. Behav Brain Res 165:63–71

    Article  CAS  PubMed  Google Scholar 

  49. Lu R, Hu CP, Peng J, Deng HW, Li YJ (2001) Role of calcitonin gene-related peptide in ischemic preconditioning in diabetic hearts. Clin Exp Pharmacol Physiol 28:392–396

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

This study was supported by the Foundation from Science and Technology Commission of Dongli District, Tianjin City (No. ANSF200801).

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Authors and Affiliations

  1. Department of Psychiatry, Anning Hospital of Tianjin City, No. 20 Yongping Lane, Dongli District, Tianjin, 300300, China

    Chuanjun Zhuo, Yufen Wang & Yuhui Chen

  2. Department of Psychiatry, the 261st Hospital of Chinese People’s Liberation Army, Haidian District, Beijing, 100094, China

    Ying Wang & Xiaohui Wang

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  1. Chuanjun Zhuo
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  4. Yufen Wang
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Correspondence to Yuhui Chen.

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Chuanjun Zhuo and Ying Wang contributed equally to this work.

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Zhuo, C., Wang, Y., Wang, X. et al. Cardioprotection by ischemic postconditioning is abolished in depressed rats: role of Akt and signal transducer and activator of transcription-3. Mol Cell Biochem 346, 39–47 (2011). https://doi.org/10.1007/s11010-010-0589-0

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