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Role of inflammation, oxidative stress, and autonomic nervous system activation during the development of right and left cardiac remodeling in experimental pulmonary arterial hypertension

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Abstract

This study investigated the impact of experimental pulmonary arterial hypertension (PAH) progression by evaluating morphometric and functional parameters, oxidative stress, autonomic nervous system (ANS) activation, and inflammation in the right (RV) and left (LV) ventricles. Male rats were first divided into two groups: monocrotaline (MCT) and control. The MCT group received a single MCT injection (60 mg/kg, intraperitoneal), while control received saline. The MCT and control groups were further divided into four cohorts based on how long they were observed: 1, 2, 3, and 4 weeks. Animals were submitted to echocardiographic and hemodynamic analysis. RV and LV were used for morphometric, biochemical, and histological measurements. Autonomic modulation was evaluated by cardiac spectral analysis, considering two components: low frequency (LF) and high frequency (HF). Lung and liver weight was used for morphometric analysis. MCT induced 100% mortality at 4 weeks. In the RV, disease progression led to mild inflammation and enhanced reactive oxygen species (ROS) in week 1, followed by moderate inflammation, ROS production, and hypertrophy in week 2. By week 3, there was moderate inflammation, oxidative stress, and ANS imbalance, with development of right heart dysfunction. LV biochemical changes and inflammation were observed at week 3. The initial changes appeared to be related to inflammation and ROS, and the later ones to inflammation, oxidative stress, and ANS imbalance in MCT animals. This study reinforces the severity of the disease in the RV, the late effects in the LV, and the role of ANS imbalance in the development of heart dysfunction.

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References

  1. Ishikawa M, Sato N, Asai K et al (2009) Effects of a pure alpha/beta-adrenergic receptor blocker on monocrotaline-induced pulmonary arterial hypertension with right ventricular hypertrophy in rats. Circ J 73:2337–2341

    Article  CAS  PubMed  Google Scholar 

  2. Gatzoulis MA, Adatia I, Celermajer D et al (2013) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 62:D34–D41. https://doi.org/10.1016/J.JACC.2013.10.029

    Article  PubMed  Google Scholar 

  3. Guignabert C, Tu L, Girerd B et al (2015) New molecular targets of pulmonary vascular remodeling in pulmonary arterial hypertension: importance of endothelial communication. Chest 147:529–537. https://doi.org/10.1378/chest.14-0862

    Article  PubMed  Google Scholar 

  4. Humbert M, Lau EMT, Montani D et al (2014) Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation 130:2189–2208. https://doi.org/10.1161/CIRCULATIONAHA.114.006974

    Article  PubMed  Google Scholar 

  5. Campian ME, Hardziyenka M, de Bruin K et al (2010) Early inflammatory response during the development of right ventricular heart failure in a rat model. Eur J Heart Fail 12:653–658. https://doi.org/10.1093/eurjhf/hfq066

    Article  CAS  PubMed  Google Scholar 

  6. DeMarco VG, Whaley-Connell AT, Sowers JR et al (2010) Contribution of oxidative stress to pulmonary arterial hypertension. World J Cardiol 2:316. https://doi.org/10.4330/wjc.v2.i10.316

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF (2009) The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest 135:794–804. https://doi.org/10.1378/chest.08-0492

    Article  CAS  PubMed  Google Scholar 

  8. Enache I, Charles A-L, Bouitbir J et al (2013) Skeletal muscle mitochondrial dysfunction precedes right ventricular impairment in experimental pulmonary hypertension. Mol Cell Biochem 373:161–170. https://doi.org/10.1007/s11010-012-1485-6

    Article  CAS  PubMed  Google Scholar 

  9. Vaillancourt M, Chia P, Sarji S et al (2017) Autonomic nervous system involvement in pulmonary arterial hypertension. Respir Res 18:201. https://doi.org/10.1186/s12931-017-0679-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Velez-Roa S, Ciarka A, Najem B et al (2004) Increased sympathetic nerve activity in pulmonary artery hypertension. Circulation 110:1308–1312. https://doi.org/10.1161/01.CIR.0000140724.90898.D3

    Article  PubMed  Google Scholar 

  11. Rigatto K, Casali KR, Shenoy V et al (2013) Diminazene aceturate improves autonomic modulation in pulmonary arterial hypertension. Eur J Pharmacol 713:89–93. https://doi.org/10.1016/j.ejphar.2013.04.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. de Lima-Seolin BG, Colombo R, Bonetto JHP et al (2017) Bucindolol improves right ventricle function in rats with pulmonary arterial hypertension through the reversal of autonomic imbalance. Eur J Pharmacol 798:57–65. https://doi.org/10.1016/j.ejphar.2016.12.028

    Article  CAS  PubMed  Google Scholar 

  13. Williams DP, Koenig J, Carnevali L et al (2019) Heart rate variability and inflammation: a meta-analysis of human studies. Brain Behav Immun. https://doi.org/10.1016/J.BBI.2019.03.009

    Article  PubMed  PubMed Central  Google Scholar 

  14. Sztuka K, Jasińska-Stroschein M (2017) Animal models of pulmonary arterial hypertension: a systematic review and meta-analysis of data from 6126 animals. Pharmacol Res 125:201–214. https://doi.org/10.1016/j.phrs.2017.08.003

    Article  PubMed  Google Scholar 

  15. Dell’Italia LJ (1998) Ventricular interdependence: Significant left ventricular contributions to right ventricular systolic function. Prog Cardiovasc Dis 40:289–308. https://doi.org/10.1016/S0033-0620(98)80049-2

    Article  PubMed  Google Scholar 

  16. Sanchez-Quintana D, Garcia-Martinez V, Hurle JM (1990) Myocardial fiber architecture in the human heart. Anatomical demonstration of modifications in the normal pattern of ventricular fiber architecture in a malformed adult specimen. Acta Anat (Basel) 138:352–358

    Article  CAS  Google Scholar 

  17. Smerup M, Nielsen E, Agger P et al (2009) The three-dimensional arrangement of the myocytes aggregated together within the mammalian ventricular myocardium. Anat Rec Adv Integr Anat Evol Biol 292:1–11. https://doi.org/10.1002/ar.20798

    Article  Google Scholar 

  18. Rudski LG, Lai WW, Afilalo J et al (2010) Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 23:685–713. https://doi.org/10.1016/j.echo.2010.05.010

    Article  PubMed  Google Scholar 

  19. Urboniene D, Haber I, Fang Y-H et al (2010) Validation of high-resolution echocardiography and magnetic resonance imaging vs. high-fidelity catheterization in experimental pulmonary hypertension. Am J Physiol Cell Mol Physiol 299:L401–L412. https://doi.org/10.1152/ajplung.00114.2010

    Article  CAS  Google Scholar 

  20. Nozawa E, Kanashiro RM, Murad N et al (2006) Performance of two-dimensional Doppler echocardiography for the assessment of infarct size and left ventricular function in rats. Braz J Med Biol Res 39:687–695. https://doi.org/10.1590/S0100-879X2006000500016

    Article  CAS  PubMed  Google Scholar 

  21. Tavares AMV, da Rosa Araújo AS, Baldo G et al (2010) Bone marrow derived cells decrease inflammation but not oxidative stress in an experimental model of acute myocardial infarction. Life Sci 87:699–706. https://doi.org/10.1016/J.LFS.2010.10.008

    Article  CAS  PubMed  Google Scholar 

  22. Peron APON, Saraiva RM, Antonio EL, Tucci PJF (2006) A função mecânica do miocárdio remanescente a um infarto do miocárdio é normal durante o período de cicatrização, embora exista insuficiência cardíaca. Arq Bras Cardiol 86:105–112. https://doi.org/10.1590/S0066-782X2006000200005

    Article  PubMed  Google Scholar 

  23. Malliani A, Pagani M, Lombardi F, Cerutti S (1991) Cardiovascular neural regulation explored in the frequency domain. Circulation 84:482–492. https://doi.org/10.1161/01.cir.84.2.482

    Article  CAS  PubMed  Google Scholar 

  24. Montano N, Ruscone TG, Porta A et al (1994) Power spectrum analysis of heart rate variability to assess the changes in sympathovagal balance during graded orthostatic tilt. Circulation 90:1826–1831. https://doi.org/10.1161/01.cir.90.4.1826

    Article  CAS  PubMed  Google Scholar 

  25. Farahmand F, Hill MF, Singal PK (2004) Antioxidant and oxidative stress changes in experimental cor pulmonale. Mol Cell Biochem 260:21–29

    Article  PubMed  Google Scholar 

  26. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  27. Pick E, Keisari Y (1980) A simple colorimetric method for the measurement of hydrogen peroxide produced by cells in culture. J Immunol Methods 38:161–170. https://doi.org/10.1016/0022-1759(80)90340-3

    Article  CAS  PubMed  Google Scholar 

  28. Buege JA, Aust SD (1978) [30] Microsomal lipid peroxidation. Methods Enzymol 52:302–310. https://doi.org/10.1016/S0076-6879(78)52032-6

    Article  CAS  PubMed  Google Scholar 

  29. SL M (1985) Handbook of Methods for Oxygen Radical Research

  30. Aebi H (1984) [13] Catalase in vitro. Methods Enzymol 105:121–126. https://doi.org/10.1016/S0076-6879(84)05016-3

    Article  CAS  PubMed  Google Scholar 

  31. Drabkin DL, Austin J (1935) Spectrophotometry of HbNO and SHb. J Biol Chem 112:51–65

    CAS  Google Scholar 

  32. Flohé L, Günzler WA (1984) [12] Assays of glutathione peroxidase. Methods Enzymol 105:114–120. https://doi.org/10.1016/S0076-6879(84)05015-1

    Article  PubMed  Google Scholar 

  33. Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77. https://doi.org/10.1016/0003-9861(59)90090-6

    Article  CAS  PubMed  Google Scholar 

  34. Stefanon I, Valero-Muñoz M, Fernandes AA et al (2013) Left and right ventricle late remodeling following myocardial infarction in rats. PLoS ONE 8:e64986. https://doi.org/10.1371/journal.pone.0064986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li C, Deng W, Liao X et al (2013) The effects and mechanism of ginsenoside Rg1 on myocardial remodeling in an animal model of chronic thromboembolic pulmonary hypertension. Eur J Med Res 18:16. https://doi.org/10.1186/2047-783X-18-16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bruce E, Shenoy V, Rathinasabapathy A et al (2015) Selective activation of angiotensin AT2 receptors attenuates progression of pulmonary hypertension and inhibits cardiopulmonary fibrosis. Br J Pharmacol 172:2219–2231. https://doi.org/10.1111/bph.13044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Montani D, Günther S, Dorfmüller P et al (2013) Pulmonary arterial hypertension. Orphanet J Rare Dis 8:97. https://doi.org/10.1186/1750-1172-8-97

    Article  PubMed  PubMed Central  Google Scholar 

  38. Gomez-Arroyo JG, Farkas L, Alhussaini AA et al (2012) The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Cell Mol Physiol 302:L363–L369. https://doi.org/10.1152/ajplung.00212.2011

    Article  CAS  Google Scholar 

  39. Hessel MHM, Steendijk P, den Adel B et al (2006) Characterization of right ventricular function after monocrotaline-induced pulmonary hypertension in the intact rat. Am J Physiol Circ Physiol 291:H2424–H2430. https://doi.org/10.1152/ajpheart.00369.2006

    Article  CAS  Google Scholar 

  40. Zimmer A, Teixeira RB, Bonetto JHP et al (2017) Effects of aerobic exercise training on metabolism of nitric oxide and endothelin-1 in lung parenchyma of rats with pulmonary arterial hypertension. Mol Cell Biochem 429:73–89. https://doi.org/10.1007/s11010-016-2937-1

    Article  CAS  PubMed  Google Scholar 

  41. Leichsenring-Silva F, Tavares AMV, Mosele F et al (2011) Association of the time course of pulmonary arterial hypertension with changes in oxidative stress in the left ventricle. Clin Exp Pharmacol Physiol 38:804–810. https://doi.org/10.1111/j.1440-1681.2011.05608.x

    Article  CAS  PubMed  Google Scholar 

  42. Gonçalves H, Henriques-Coelho T, Bernardes J et al (2010) Analysis of heart rate variability in a rat model of induced pulmonary hypertension. Med Eng Phys 32:746–752. https://doi.org/10.1016/j.medengphy.2010.04.018

    Article  PubMed  Google Scholar 

  43. Wensel R, Jilek C, Dorr M et al (2009) Impaired cardiac autonomic control relates to disease severity in pulmonary hypertension. Eur Respir J 34:895–901. https://doi.org/10.1183/09031936.00145708

    Article  CAS  PubMed  Google Scholar 

  44. Fauchier L, Babuty D, Melin A et al (2004) Heart rate variability in severe right or left heart failure: the role of pulmonary hypertension and resistances. Eur J Heart Fail 6:181–185. https://doi.org/10.1016/j.ejheart.2003.09.007

    Article  PubMed  Google Scholar 

  45. Seyfarth T, Gerbershagen H-P, Giessler C et al (2000) The cardiac β-adrenoceptor-G-protein(s)-adenylyl cyclase system in monocrotaline-treated rats. J Mol Cell Cardiol 32:2315–2326. https://doi.org/10.1006/jmcc.2000.1262

    Article  CAS  PubMed  Google Scholar 

  46. Ishikawa S, Honda M, Yamada S et al (1991) Biventricular down-regulation of beta-adrenergic receptors in right ventricular hypertrophy induced by monocrotaline. Jpn Circ J 55:1077–1085

    Article  CAS  PubMed  Google Scholar 

  47. Su DF, Miao CY (2001) Blood pressure variability and organ damage. Clin Exp Pharmacol Physiol 28:709–715

    Article  CAS  PubMed  Google Scholar 

  48. Khaper N, Bryan S, Dhingra S et al (2010) Targeting the vicious inflammation-oxidative stress cycle for the management of heart failure. Antioxid Redox Signal 13:1033–1049. https://doi.org/10.1089/ars.2009.2930

    Article  CAS  PubMed  Google Scholar 

  49. Palace VP, Khaper N, Qin Q, Singal PK (1999) Antioxidant potentials of vitamin A and carotenoids and their relevance to heart disease. Free Radic Biol Med 26:746–761. https://doi.org/10.1016/S0891-5849(98)00266-4

    Article  CAS  PubMed  Google Scholar 

  50. Schreckenberg R, Rebelo M, Deten A et al (2015) Specific mechanisms underlying right heart failure: the missing upregulation of superoxide dismutase-2 and its decisive role in antioxidative defense. Antioxid Redox Signal 23:1220–1232. https://doi.org/10.1089/ars.2014.6139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Borchi E, Bargelli V, Stillitano F et al (2010) Enhanced ROS production by NADPH oxidase is correlated to changes in antioxidant enzyme activity in human heart failure. Biochim Biophys Acta 1802:331–338. https://doi.org/10.1016/j.bbadis.2009.10.014

    Article  CAS  PubMed  Google Scholar 

  52. Emam SE, Ando H, Lila ASA et al (2018) Liposome co-incubation with cancer cells secreted exosomes (extracellular vesicles) with different proteins expressions and different uptake pathways. Sci Rep 8:14493. https://doi.org/10.1038/s41598-018-32861-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Aliotta JM, Pereira M, Wen S et al (2016) Exosomes induce and reverse monocrotaline-induced pulmonary hypertension in mice. Cardiovasc Res 110:319–330. https://doi.org/10.1093/cvr/cvw054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yáñez-Mó M, Siljander PR-M, Andreu Z et al (2015) Biological properties of extracellular vesicles and their physiological functions. J Extracell vesicles 4:27066. https://doi.org/10.3402/jev.v4.27066

    Article  PubMed  Google Scholar 

  55. Triposkiadis F, Karayannis G, Giamouzis G et al (2009) The sympathetic nervous system in heart failure. J Am Coll Cardiol 54:1747–1762. https://doi.org/10.1016/j.jacc.2009.05.015

    Article  CAS  PubMed  Google Scholar 

  56. Abboud FM, Singh MV (2017) Autonomic regulation of the immune system in cardiovascular diseases. Adv Physiol Educ 41:578–593. https://doi.org/10.1152/advan.00061.2017

    Article  PubMed  PubMed Central  Google Scholar 

  57. Bezerra OC, França CM, Rocha JA et al (2017) Cholinergic stimulation improves oxidative stress and inflammation in experimental myocardial infarction. Sci Rep 7:13687. https://doi.org/10.1038/s41598-017-14021-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Financial assistance from National Council of Technological and Scientific Development, Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. Veterinary medical support from André Ricardo Ribeiro Belló.

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Authors and Affiliations

  1. Laboratory of Cardiovascular Physiology and Reactive Oxygen Species, Physiology Department, Institute of Basic Health Science, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil

    A. Zimmer, R. B. Teixeira, J. H. P. Bonetto, A. C. Bahr, P. Türck, A. L. de Castro, C. Campos-Carraro, T. R. Fernandes-Piedras, G. Baldo, A. S. Araujo & A. Belló-Klein

  2. Faculty of Dentistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil

    F. Visioli

  3. Institute of Sciences and Technology, Universidade Federal de São Paulo, São Paulo, Brazil

    K. R. Casali & C. M. C. Scassola

  4. Cell Pathophysiology Laboratory, Department of Physiology and Pathophysiology, Institute of Cardiovascular Sciences, Winnipeg, Canada

    P. Singal

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Zimmer, A., Teixeira, R.B., Bonetto, J.H.P. et al. Role of inflammation, oxidative stress, and autonomic nervous system activation during the development of right and left cardiac remodeling in experimental pulmonary arterial hypertension. Mol Cell Biochem 464, 93–109 (2020). https://doi.org/10.1007/s11010-019-03652-2

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