Prehypertension exercise training attenuates hypertension and cardiac hypertrophy accompanied by temporal changes in the levels of angiotensin II and angiotensin (1-7)


Appropriate exercise training (ExT) has been shown to decrease high blood pressure. Accumulating data have indicated the beneficial effects of ExT on prehypertension. This study tested whether prehypertension ExT protects against hypertension and cardiac remodeling in spontaneously hypertensive rats (SHR) and explored the underlying mechanisms by examining the cardiac angiotensin-converting enzyme (ACE) and ACE2 signaling axes. Low-intensity ExT was started in male SHR and control Wistar-Kyoto rats prior to the onset of hypertension and maintained for 8 or 16 weeks. Blood pressure (BP) was measured biweekly by the tail-cuff method. Cardiac function and remodeling were assessed, and changes in the ACE and ACE2 axes were examined after the final ExT session. The results showed that prehypertension ExT slowed the onset and progression of hypertension in SHR. In parallel, hypertrophy in the hearts of hypertensive rats was attenuated, myocardial fibrosis was reduced, and impairment of left ventricular diastolic function was reduced. In the SHR myocardium, the levels of components involved in the ACE–Ang II–AT1 axis were homogeneously and progressively increased, whereas those involved in the ACE2–Ang(1-7)–MAS axis were heterogeneously decreased. Different temporal responses were observed for the key effectors Ang II and Ang(1-7). Myocardial Ang II levels were progressively increased in SHR and were consistently reduced by ExT. By contrast, Ang(1-7) decreased only after 16 weeks of sedentariness, and this decrease was abolished by ExT. In addition, 16 weeks of ExT increased the levels of Ang(1-7) in normotensive control rats. In summary, prehypertension ExT attenuates hypertension and cardiac remodeling. Downregulation of Ang II seems to serve as a protective mechanism during ExT, while upregulation of Ang(1-7) is induced after a relatively long period of ExT.

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  1. 1.

    Ferrario CM. Cardiac remodeling and RAS inhibition. Ther Adv Cardiovasc Dis. 2016;10:162–71.

  2. 2.

    Weber MA. New opportunities in cardiovascular patient management: a survey of clinical data on the combination of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Am J Cardiol. 2007;100:45J–52J.

  3. 3.

    Kolasinska-Malkowska K, Filipiak KJ, Gwizdala A, Tykarski A. Current possibilities of ACE inhibitor and ARB combination in arterial hypertension and its complications. Expert Rev Cardiovasc Ther. 2008;6:759–71.

  4. 4.

    Santos RA, Ferreira AJ, Verano-Braga T, Bader M. Angiotensin-converting enzyme 2, angiotensin-(1-7) and MAS: new players of the renin-angiotensin system. J Endocrinol. 2013;216:R1–R17.

  5. 5.

    Ferreira AJ, Shenoy V, Qi Y, Fraga-Silva RA, Santos RA, Katovich MJ, et al. Angiotensin-converting enzyme 2 activation protects against hypertension-induced cardiac fibrosis involving extracellular signal-regulated kinases. Exp Physiol. 2011;96:287–94.

  6. 6.

    Gromotowicz-Poplawska A, Szoka P, Kolodziejczyk P, Kramkowski K, Wojewodzka-Zelezniakowicz M, Chabielska E. New agents modulating the renin-angiotensin-aldosterone system—will there be a new therapeutic option? Exp Biol Med (Maywood). 2016;241:1888–99.

  7. 7.

    Díez-Freire C, Vázquez J, Correa de Adjounian MF, Ferrari MF, Yuan L, Silver X, et al. ACE2 gene transfer attenuates hypertension-linked pathophysiological changes in the SHR. Physiol Genomics. 2006;27:12–9.

  8. 8.

    Mercure C, Yogi A, Callera GE, Aranha AB, Bader M, Ferreira AJ, et al. Angtiotensin(1-7) blunts hypertensive cardiac remodeling by a direct effect on the heart. Circ Res. 2008;103:1319–26.

  9. 9.

    Pei Z, Meng R, Li G, Yan G, Xu C, Zhuang Z, et al. Angiotensin-(1-7) ameliorates myocardial remodeling and interstitial fibrosis in spontaneous hypertension: role of MMPs/TIMPs. Toxicol Lett. 2010;199:173–81.

  10. 10.

    Fagard RH. Exercise therapy in hypertensive cardiovascular disease. Prog Cardiovasc Dis. 2011;53:404–11.

  11. 11.

    Schlüter KD, Schreckenberg R, da Costa, Rebelo RM. Interaction between exercise and hypertension in spontaneously hypertensive rats: a meta-analysis of experimental studies. Hypertens Res. 2010;33:1155–61.

  12. 12.

    Hegde SM, Solomon SD. Influence of physical activity on hypertension and cardiac structure and function. Curr Hypertens Rep. 2015;17:77–85.

  13. 13.

    Garciarena CD, Pinilla OA, Nolly MB, Laguens RP, Escudero EM, Cingolani HE, et al. Endurance training in the spontaneously hypertensive rat conversion of pathological into physiological cardiac hypertrophy. Hypertension. 2009;53:708–14.

  14. 14.

    Filho AG, Ferreira AJ, Santos SH, Neves SR, Silva Camargos ER, Becker LK, et al. Selective increase of angiotensin(1-7) and its receptor in heart of spontaneously hypertensive rats subjected to physical training. Exp Physiol. 2008;93:589–98.

  15. 15.

    Silva SD Jr, Jara ZP, Peres R, Lima LS, Scavone C, Montezano AC, et al. Temporal changes in cardiac oxidative stress, inflammation and remodeling induced by exercise in hypertension: Role for local angiotensin II reduction. PLoS ONE. 2017;12:e0189535.

  16. 16.

    Pescatello LS, MacDonald HV, Lamberti L, Johnson BT. Exercise for hypertension: a prescription update integrating existing recommendations with emerging research. Curr Hypertens Rep. 2015;17:87.

  17. 17.

    Williamson W, Foster C, Reid H, Kelly P, Lewandowski AJ, Boardman H, et al. Will exercise advice be sufficient for treatment of young adults with prehypertension and hypertension? A systematic review and meta-analysis. Hypertension. 2016;68:78–87.

  18. 18.

    Xing W, Li Y, Zhang H, Mi C, Hou Z, Quon MJ, et al. Improvement of vascular insulin sensitivity by downregulation of GRK2 mediates exercise-induced alleviation of hypertension in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol. 2013;305:H1111–9.

  19. 19.

    Véras-Silva AS, Mattos KC, Gava NS, Brum PC, Negrão CE, Krieger EM. Low-intensity exercise training decreases cardiac output and hypertension in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol. 1997;273:H2627–31.

  20. 20.

    Qiu F, Liu X, Zhang Y, Wu Y, Xiao D, Shi L. Aerobic exercise enhanced endothelium-dependent vasorelaxation in mesenteric arteries in spontaneously hypertensive rats: the role of melatonin. Hypertens Res. 2018;41:718–29.

  21. 21.

    Wu JA, Bu L, Gong H, Jiang G, Li L, Ma H, et al. Effects of heart rate and anesthetic timing on high resolution echocardiographic assessment under isoflurane anesthesia in mice. J Ultrasound Med. 2010;29:1771–8.

  22. 22.

    Peng H, Carretero OA, Liao TD, Peterson EL, Rhaleb NE. Role of n-acetyl-seryl- aspartyl-lysyl-proline in the antifibrotic and anti-Inflammatory effects of the angiotensin-converting enzyme inhibitor captopril in hypertension. Hypertension. 2007;49:695–703.

  23. 23.

    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402–8.

  24. 24.

    Lin L, Liu X, Xu J, Weng L, Ren J, Ge J, et al. MAS receptor mediates cardioprotection of angiotensin-(1-7) against angiotensin II-induced cardiomyocyte autophagy and cardiac remodelling through inhibition of oxidative stress. J Cell Mol Med. 2016;20:48–57.

  25. 25.

    Wysocki J, Ortiz-Melo DI, Mattocks NK, Xu K, Prescott J, Evora K, et al. ACE2 deficiency increases NADPH-mediated oxidative stress in the kidney. Physiol Rep. 2014;2:e00264.

  26. 26.

    Huang T, Long M, Huo B. Competitive binding to cuprous ions of protein and BCA in the bicinchoninic acid protein assay. Open Biomed Eng J. 2010;4:271–8.

  27. 27.

    Soya H, Mukai A, Deocaris CC, Ohiwa N, Chang H, Nishijima T, et al. Threshold-like pattern of neuronal activation in the hypothalamus during treadmill running: establishment of a minimum running stress (MRS) rat model. Neurosci Res. 2007;58:341–8.

  28. 28.

    Thompson PD, Crouse SF, Goodpaster B, Kelley D, Moyna N, Pescatello L. The acute versus the chronic response to exercise. Med Sci Sports Exerc. 2001;33:S438–45.

  29. 29.

    Campos JC, Fernandes T, Bechara LR, da Paixão NA, Brum PC, de Oliveira EM, et al. Increased clearance of reactive aldehydes and damaged proteins in hypertension-induced compensated cardiac hypertrophy: impact of exercise training. Oxid Med Cell Longev. 2015;2015:464195.

  30. 30.

    Muñoz MV, Backman W, Sam F. Murine models of heart failure with preserved ejection fraction: a “fishing expedition”. JACC Basic Transl Sci. 2017;2:770–89.

  31. 31.

    Shah SJ, Aistrup GL, Gupta DK, O’Toole MJ, Nahhas AF, Schuster D, et al. Ultrastructural and cellular basis for the development of abnormal myocardial mechanics during the transition from hypertension to heart failure. Am J Physiol Heart Circ Physiol. 2014;306:H88–H100.

  32. 32.

    Hamasaki H. Exercise and gut microbiota: clinical implications for the feasibility of Tai Chi. J Integr Med. 2017;15:270–81.

  33. 33.

    Sousa CM, Coimbra D, Machado J, Greten HJ. Effects of self-administered exercises based on Tuina techniques on musculoskeletal disorders of professional orchestra musicians: a randomized controlled trial. J Integr Med. 2015;13:314–8.

  34. 34.

    Rossoni LV, Oliveira RA, Caffaro RR, Miana M, Sanz-Rosa D, Koike MK, et al. Cardiac benefits of exercise training in aging spontaneously hypertensive rats. J Hypertens. 2011;29:2349–58.

  35. 35.

    Fagard RH. Impact of different sports and training on cardiac structure and function. Cardiol Clin. 1997;15:397–412.

  36. 36.

    Boissiere J, Eder V, Machet MC, Courteix D, Bonnet P. Moderate exercise training does not worsen left ventricle remodeling and function in untreated severe hypertensive rats. J Appl Physiol. 2008;104:321–7.

  37. 37.

    Svetkey LP. Management of prehypertension. Hypertension. 2005;45:1056–61.

  38. 38.

    Beck DT, Martin JS, Casey DP, Braith RW. Exercise training improves endothelial function in young prehypertension. J Hum Hypertens. 2014;28:303–9.

  39. 39.

    Beck DT, Martin JS, Casey DP, Braith RW. Exercise training reduces peripheral arterial stiffness and myocardial oxygen demand in young prehypertensive subjects. Am J Hypertens. 2013;26:1093–102.

  40. 40.

    Kwak HB, Kim JH, Joshi K, Yeh A, Martinez DA, Lawler JM. ExT reduces fibrosis and matrix metalloproteinase dysregulation in the aging rat heart. FASEB J. 2011;25:1106–17.

  41. 41.

    Grotendorst GR, Rahmanie H, Duncan MR. Combinatorial signaling pathways determine fibroblast proliferation and myofibroblast differentiation. FASEB J. 2004;18:469–79.

  42. 42.

    Oh MS, Cho SJ, Sung J, Hong KP. Higher blood pressure during light exercise is associated with increased left ventricular mass index in normotensive subjects. Hypertens Res. 2018;41:382–7.

  43. 43.

    Nguyen Dinh Cat A, Montezano AC, Burger D, Touyz RM. Angiotensin II, NADPH oxidase, and redox signaling in the vasculature. Antioxid Redox Signal. 2013;19:1110–20.

  44. 44.

    Paul M, Mehr AP, Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev. 2006;86:747–803.

  45. 45.

    Gu Q, Wang B, Zhang XF, Ma YP, Liu JD, Wang XZ. Contribution of rennin angiotensin system to exercise-induced attenuation of aortic remodeling and improvement of endothelial function in spontaneously hypertensive rats. Cardiovasc Pathol. 2014;23:298–305.

  46. 46.

    Agarwal D, Welsch MA, Keller JN, Francis J. Chronic exercise modulates RAS components and improves balance between pro- and anti-inflammatory cytokines in the brain of SHR. Basic Res Cardiol. 2011;106:1069–85.

  47. 47.

    Bouressam ML, Lartaud I, Dupuis F, Lecat S. No answer to the lack of specificity: mouse monoclonal antibody targeting the angiotensin II type 1 receptor AT1 fails to recognize its target. Naunyn Schmiede Arch Pharm. 2018;391:883–9.

  48. 48.

    Benicky J, Hafko R, Sanchez-Lemus E, Aguilera G, Saavedra JM. Six commercially available angiotensin II AT1 receptor antibodies are non-specific. Cell Mol Neurobiol. 2012;32:1353–65.

  49. 49.

    Herrera M, Sparks MA, Alfonso-Pecchio AR, Harrison-Bernard LM, Coffman TM. Lack of specificity of commercial antibodies leads to misidentification of angiotensin type 1 receptor protein. Hypertension. 2013;61:e32.

  50. 50.

    Burghi V, Fernández NC, Gándola YB, Piazza VG, Quiroga DT, Guilhen Mario É, et al. Validation of commercial Mas receptor antibodies for utilization in western blotting, immunofluorescence and immunohistochemistry studies. PLoS ONE. 2017;12:e0183278.

  51. 51.

    Bertagnolli M, Schenkel PC, Campos C, Mostarda CT, Casarini DE, Belló-Klein A, et al. Exercise training reduces sympathetic modulation on cardiovascular system and cardiac oxidative stress in spontaneously hypertensive rats. Am J Hypertens. 2008;21:1188–93.

  52. 52.

    de Andrade LH, de Moraes WM, Matsuo Junior EH, de Orleans Carvalho de Moura E, Antunes HK, Montemor J, et al. Aerobic exercise training improves oxidative stress and ubiquitin proteasome system activity in heart of spontaneously hypertensive rats. Mol Cell Biochem. 2015;402:193–202.

  53. 53.

    Zhang M, Qin DN, Suo YP, Su Q, Li HB, Miao YW, et al. Endogenous hydrogen peroxide in the hypothalamic paraventricular nucleus regulates neurohormonal excitation in high salt-induced hypertension. Toxicol Lett. 2015;235:206–15.

  54. 54.

    Luo H, Wang X, Chen C, Wang J, Zou X, Li C, et al. Oxidative stress causes imbalance of renal renin angiotensin system (RAS) components and hypertension in obese Zucker rats. J Am Heart Assoc. 2015;4:e001559.

  55. 55.

    Su Q, Qin DN, Wang FX, Ren J, Li HB, Zhang M, et al. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin-angiotensin system and proinflammatory cytokines in hypertension. Toxicol Appl Pharm. 2014;276:115–20.

  56. 56.

    Jia LL, Kang YM, Wang FX, Li HB, Zhang Y, Yu XJ, et al. Exercise training attenuates hypertension and cardiac hypertrophy by modulating neurotransmitters and cytokines in hypothalamic paraventricular nucleus. PLoS ONE. 2014;9:e85481.

  57. 57.

    Sriramula S, Cardinale JP, Francis J. Inhibition of TNF in the brain reverses alterations in RAS components and attenuates angiotensin II-induced hypertension. PLoS ONE. 2013;8:e63847.

  58. 58.

    Zucker IH, Xiao L, Haack KK. The central renin-angiotensin system and sympathetic nerve activity in chronic heart failure. Clin Sci (Lond). 2014;126:695–706.

  59. 59.

    Liu D, Gao L, Roy SK, Cornish KG, Zucker IH. Neuronal angiotensin II type 1 receptor upregulation in heart failure: activation of activator protein 1 and Jun N-terminal kinase. Circ Res. 2006;99:1004–11.

  60. 60.

    Fernandes T, Hashimoto NY, Magalhães FC, Fernandes FB, Casarini DE, Carmona AK, et al. Aerobic exercise training-induced left ventricular hypertrophy involves regulatory MicroRNAs, decreased angiotensin-converting enzyme-angiotensin II, and synergistic regulation of angiotensin-converting enzyme 2-angiotensin (1-7). Hypertension. 2011;58:182–9.

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This work was supported by the National Natural Science Foundation of China (No. 81372111, 81670295) and the Natural Science Foundation of Fujian Province of China (No. 2014J01339).

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Correspondence to Yan-Xia Pan.

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  • Exercise training
  • Prehypertension
  • Cardiac remodeling
  • Renin–angiotensin system
  • Hypertension