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Effects of emotional and physiological stress on plaque instability in apolipoprotein E knockout mice

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Abstract

In the present study, we sought to investigate the effects of emotional and physiological stress on plaque instability in atherosclerosis. We used different stress-treated apolipoprotein E (ApoE)-deficient mice, which have been shown to spontaneously develop atherosclerosis with features similar to those seen in humans, as an animal model. Morphology study showed that emotional stress (ES) obviously promoted the development of atherosclerotic plaques and plaque instability evidenced by significantly increasing plaque size, plaque-to-surface ratio and plaque calcification, and enhancing the frequency of large necrotic core and medial erosion compared with control ApoE−/− mice (P < 0.01). Physiological stress (PS) treatment alone did not affect the plaque stability compared with control ApoE−/− mice (P > 0.05). However, the combination of ES and PS treatment (CS) initiated much stronger plaque instability compared with ES treatment alone (P < 0.01), increased the frequency of thin fibrous caps, and even triggered plaque rupture and buried fibrous cap. Immunohistochemical analysis indicated that both ES and CS treatment led to an increase in the accumulation of macrophages and T cells and a decrease of smooth muscle cells, reflecting an unstable atherosclerotic plaque phenotype, in the atherosclerotic lesions in ApoE−/− mice. PS alone did not affect plaque cellular components. Similarly, CS-mediated changes in atherosclerotic plaque composition were stronger than that caused by ES alone (P < 0.01). Taken together, ES treatment alone is sufficient to promote plaque instability. PS alone does not affect atherosclerotic plaque development, but can potentiate ES-mediated plaque destabilization.

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References

  1. Abedin M, Tintut Y, Demer LL (2004) Vascular calcification: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol 24:1161–1170

    Article  PubMed  CAS  Google Scholar 

  2. Barnett SA (1958) Physiological effects of social stress in wild rats. I. The adrenal cortex. J Psychosom Res 3(1):1–11

    Article  PubMed  CAS  Google Scholar 

  3. Barnett SA, Eaton JC, Mc CH (1960) Physiological effects of “social stress” in wild rats—II. Liver glycogen and blood glucose. J Psychosom Res 4:251–260

    Article  PubMed  CAS  Google Scholar 

  4. Bauriedel G, Hutter R, Welsch U, Bach R, Sievert H, Lüderitz B (1999) Role of smooth muscle cell death in advanced coronary primary lesions: implications for plaque instability. Cardiovasc Res 41:480–488

    Article  PubMed  CAS  Google Scholar 

  5. Berkman LF, Leo-Summers L, Horwitz RI (1992) Emotional support and survival after myocardial infarction. A prospective, population-based study of the elderly. Ann Intern Med 117:1003–1009

    PubMed  CAS  Google Scholar 

  6. Blanchard DC, Spencer RL, Weiss SM, Blanchard RJ, McEwen B, Sakai RR (1995) Visible burrow system as a model of chronic social stress: behavioral and neuroendocrine correlates. Psychoneuroendocrinology 20(2):117–134

    Article  PubMed  CAS  Google Scholar 

  7. Bosma H, Peter R, Siegrist J, Marmot M (1998) Two alternative job stress models and the risk of coronary heart disease. Am J Public Health 88:68–74

    Article  PubMed  CAS  Google Scholar 

  8. Chapman I (1960) Anatomic and clinical significance of calcification of the aortic knob visualized radiographically. Am J Cardiol 6:281–286

    Article  PubMed  CAS  Google Scholar 

  9. Clarke MC, Figg N, Maguire JJ, Davenport AP, Goddard M, Littlewood TD, Bennett MR (2006) Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis. Nat Med 12:1075–1080

    Article  PubMed  CAS  Google Scholar 

  10. Davies MJ, Thomas A (1984) Thrombosis and acute coronary–artery lesions in sudden cardiac ischemic death. N Engl J Med 310:1137–1140

    Article  PubMed  CAS  Google Scholar 

  11. Desai A, Zhao Y, Warren JS (2008) Development of atherosclerosis in Balb/c apolipoprotein E-deficient mice. Cardiovasc Pathol 17:233–240

    Article  PubMed  CAS  Google Scholar 

  12. Detrano RC, Doherty TM, Davies MJ, Stary HC (2000) Predicting coronary events with coronary calcium: pathophysiologic and clinical problems. Curr Probl Cardiol 25:374–402

    Article  PubMed  CAS  Google Scholar 

  13. Dijkstra H, Tilders FJ, Hiehle MA, Smelik PG (1992) Hormonal reactions to fighting in rat colonies: prolactin rises during defence, not during offence. Physiol Behav 51(5):961–968

    Article  PubMed  CAS  Google Scholar 

  14. Doherty TM, Detrano RC (1994) Coronary arterial calcification as an active process: a new perspective on an old problem. Calcif Tissue Int 54:224–230

    Article  PubMed  CAS  Google Scholar 

  15. Ehara S, Kobayashi Y, Yoshiyama M, Ueda M, Yoshikawa J (2006) Coronary artery calcification revisited. Atheroscler Thromb 13:31–37

    Article  Google Scholar 

  16. Haller J, Fuchs E, Halasz J, Makara GB (1999) Defeat is a major stressor in males while social instability is stressful mainly in females: towards the development of a social stress model in female rats. Brain Res Bull 50(1):33–39

    Article  PubMed  CAS  Google Scholar 

  17. Hansson GK (2001) Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol 21:1876–1890

    Article  PubMed  CAS  Google Scholar 

  18. Harris RB, Zhou J, Youngblood BD et al (1998) Effect of repeated stress on body weight and body composition of rats fed low- and high-fat diets. Am J Physiol 275(6 Pt 2):R1928–R1938

    PubMed  CAS  Google Scholar 

  19. Kolodgie FD, Gold HK, Burke AP, Fowler DR, Kruth HS, Weber DK, Farb A, Guerrero LJ, Hayase M, Kutys R, Narula J, Finn AV, Virmani R (2003) Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 349:2316–2325

    Article  PubMed  CAS  Google Scholar 

  20. Kumari M, Grahame-Clarke C, Shanks N, Marmot M, Lightman S, Vallance P (2003) Chronic stress accelerates atherosclerosis in the apolipoprotein E-deficient mouse. Stress 6:297–299

    Article  PubMed  CAS  Google Scholar 

  21. Libby P (1995) Molecular bases of the acute coronary syndromes. Circulation 91:2844–2850

    PubMed  CAS  Google Scholar 

  22. Mallick J, Stoddart DM, Jones I, Bradley AJ (1994) Behavioral and endocrinological correlates of social status in the male sugar glider (Petaurus breviceps Marsupialia: Petauridae). Physiol Behav 55(6):1131–1134

    Article  PubMed  CAS  Google Scholar 

  23. Marti O, Marti J, Armario A (1994) Effects of chronic stress on food intake in rats:influence of stressor intensity and duration of daily exposure. Physiol Behav 55(4):747–753

    Article  PubMed  CAS  Google Scholar 

  24. Martinet W, Croons V, Timmermans JP, Herman AG, De Meyer GR (2007) Nitric oxide selectively depletes macrophages in atherosclerotic plaques via induction of endoplasmic reticulum stress. Br J Pharmacol 152:493–500

    Article  PubMed  CAS  Google Scholar 

  25. McGovern PG, Pankow JS, Shahar E, Doliszny KM, Folsom AR, Blackburn H, Luepker RV (1996) Recent trends in acute coronary heart disease—mortality, morbidity, medical care, and risk factors. The Minnesota Heart Survey Investigators. N Engl J Med 334(14):884–890

    Article  PubMed  CAS  Google Scholar 

  26. Meerlo P, Overkamp GJ, Daan S, Van Den Hoofdakker RH, Koolhaas JM (1996) Changes in behaviour and body weight following a single or double social defeat in rats. Stress 1(1):21–32

    Article  PubMed  Google Scholar 

  27. Mittleman MA, Maclure M, Sherwood JB, Mulry RP, Tofler GH, Jacobs SC, Friedman R, Benson H, Muller JE (1995) Triggering of acute myocardial infarction onset by episodes of anger. Determinants of Myocardial Infarction Onset Study Investigators. Circulation 92:1720–1725

    PubMed  CAS  Google Scholar 

  28. Möller J, Hallqvist J, Diderichsen F, Theorell T, Reuterwall C, Ahlbom A (1999) Do episodes of anger trigger myocardial infarction? A case–crossover analysis in the Stockholm Heart Epidemiology Program (SHEEP). Psychosom Med 61:842–849

    PubMed  Google Scholar 

  29. O’Malley PG, Taylor AJ, Jackson JL, Doherty TM, Detrano RC (2000) Prognostic value of coronary electron-beam computed tomography for coronary heart disease events in asymptomatic populations. Am J Cardiol 85:945–948

    Article  PubMed  Google Scholar 

  30. Peeters W, Hellings WE, de Kleijn DP, de Vries JP, Moll FL, Vink A, Pasterkamp G (2009) Carotid atherosclerotic plaques stabilize after stroke: insights into the natural process of atherosclerotic plaque stabilization. Arterioscler Thromb Vasc Biol 29:128–133

    Article  PubMed  CAS  Google Scholar 

  31. Raab A, Dantzer R, Michaud B, Mormede P, Taghzouti K, Simon H, Le Moal M (1986) Behavioural, physiological and immunological consequences of social status and aggression in chronically coexisting resident-intruder dyads of male rats. Physiol Behav 36(2):223–228

    Article  PubMed  CAS  Google Scholar 

  32. 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

    PubMed  CAS  Google Scholar 

  33. Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS (1995) Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. Circulation 92:2157–2162

    PubMed  CAS  Google Scholar 

  34. Rybkin II, Zhou Y, Volaufova J et al (1997) Effect of restraint stress on food intake and body weight is determined by time of day. Am J Physiol 273(5 Pt 2):R1612–R1622

    PubMed  CAS  Google Scholar 

  35. Schmermund A, Erbel R (2001) Unstable coronary plaque and its relation to coronary calcium. Circulation 104:1682–1687

    Article  PubMed  CAS  Google Scholar 

  36. Schrijvers DM, De Meyer GR, Herman AG, Martinet W (2007) Phagocytosis in atherosclerosis: molecular mechanisms and implications for plaque progression and stability. Cardiovasc Res 73:470–480

    Article  PubMed  CAS  Google Scholar 

  37. Shah PK (2007) Molecular mechanisms of plaque instability. Curr Opin Lipidol 18:492–499

    Article  PubMed  CAS  Google Scholar 

  38. Shao F, Lin W, Wang W, Washington WC Jr, Zheng L (2003) The effect of emotional stress on the primary humoral immunity of rats. J Psychopharmacol 17:179–183

    Article  PubMed  CAS  Google Scholar 

  39. Shimizu T, Tanaka M, Yokoo H, Gondoh Y, Mizoguchi K, Matsuguchi N, Tsuda A (1994) Differential changes in rat brain noradrenaline turnover produced by continuous and intermittent restraint stress. Pharmacol Biochem Behav 49(4):905–909

    Article  PubMed  CAS  Google Scholar 

  40. Stansfeld SA, Fuhrer R, Shipley MJ, Marmot MG (2002) Psychological distress as a risk factor for coronary heart disease in the Whitehall II Study. Int J Epidemiol 31:248–255

    Article  PubMed  Google Scholar 

  41. Stary HC (2000) Natural history of calcium deposits in atherosclerosis progression and regression. Z Kardiol 89(Suppl 2):28–35

    Article  PubMed  Google Scholar 

  42. Stoll G, Bendszus M (2006) Inflammation and atherosclerosis: novel insights into plaque formation and destabilization. Stroke 37:1923–1932

    Article  PubMed  CAS  Google Scholar 

  43. Wang Q, Zeng YJ, Huo P, Hu JL, Zhang JH (2003) A specialized plug-in software module for computer-aided quantitative measurement of medical images. Med Eng Phys 25:887–892

    Article  PubMed  CAS  Google Scholar 

  44. Williams KJ, Tabas I (1995) The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol 15:551–561

    Article  PubMed  CAS  Google Scholar 

  45. Wood SK, Baez MA, Bhatnagar S, Valentino RJ (2009) Social stress-induced bladder dysfunction: potential role of corticotropin-releasing factor. Am J Physiol Regul Integr Comp Physiol 296:R1671–R1678

    Article  PubMed  CAS  Google Scholar 

  46. Zhang T, Chen Y, Liu H, Zhou Z, Zhai Y, Yang J (2010) Chronic unpredictable stress accelerates atherosclerosis through promoting inflammation in apolipoprotein E knockout mice. Thromb Res 126(5):386–392

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Hongbin Liu.

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Tao Zhang and Yongzhi Zhai equally contributed to this work and share the first authorship

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Zhang, T., Zhai, Y., Chen, Y. et al. Effects of emotional and physiological stress on plaque instability in apolipoprotein E knockout mice. J Physiol Biochem 67, 401–413 (2011). https://doi.org/10.1007/s13105-011-0090-6

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  • DOI: https://doi.org/10.1007/s13105-011-0090-6

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