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Pathophysiology of Infantile Pulmonary Arterial Hypertension Induced by Monocrotaline

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Abstract

Pediatric pulmonary arterial hypertension (PAH) presents certain specific features. In this specific age group, experimental models to study the pathophysiology of PAH are lacking. To characterize hemodynamic, morphometric, and histological progression as well as the expression of neurohumoral factors and regulators of cardiac transcription in an infantile model of PAH induced by monocrotaline (MCT), eight-day-old Wistar rats were randomly injected with MCT (30 mg/kg, sc, n = 95) or equal volume of saline solution (n = 92). Animals were instrumented for biventricular hemodynamic recording 7, 14, and 21 days after MCT, whereas samples were collected at 1, 3, 7, 14, and 21 days after MCT. Different time point postinjections were defined for further analysis. Hearts and lungs were collected for morphometric characterization, assessment of right- and left-ventricle (RV and LV) cardiomyocyte diameter and collagen type-I and type-III ratio, RV collagen volume fraction, and pulmonary vessels wall thickness. mRNA quantification was undertaken for brain natriuretic peptide (BNP), endothelin-1 (ET-1), and for cardiac transcription regulators (HOP and Islet1). Animals treated with MCT at the 8th day of life presented RV hypertrophy since day 14 after MCT injection. There were no differences on the RV collagen volume fraction or collagen type-I and type-III ratio. Pulmonary vascular remodelling and PAH were present on day 21, which were accompanied by an increased expression of BNP, ET-1, HOP, and Islet1. The infantile model of MCT-induced PAH can be useful for the study of its pathophysiology and to test new therapeutic targets in pediatric age group.

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References

  1. Adachi S, Ito H, Ohta Y, Tanaka M, Ishiyama S, Nagata M, Toyozaki T, Hirata Y, Marumo F, Hiroe M (1995) Distribution of mRNAs for natriuretic peptides in RV hypertrophy after pulmonary arterial banding. Am J Physiol 268:H162–H169

    CAS  PubMed  Google Scholar 

  2. Akazawa H, Komuro I (2003) Roles of cardiac transcription factors in cardiac hypertrophy. Circ Res 92:1079–1088

    Article  CAS  PubMed  Google Scholar 

  3. Bourdillon PD, Oakley CM (1976) Regression of primary pulmonary hypertension. Br Heart J 38:264–270

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Cai CL, Liang X, Shi Y, Chu PH, Pfaff SL, Chen J, Evans S (2003) Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell 5:877–889

    Article  CAS  PubMed  Google Scholar 

  5. Campian ME, Verberne HJ, Hardziyenka M, de Bruin K, Selwaness M, van den Hoff MJ, Ruijter JM, van Eck-Smit BL, de Bakker JM, Tan HL (2009) Serial noninvasive assessment of apoptosis during right ventricular disease progression in rats. J Nucl Med 50:1371–1377

    Article  PubMed  Google Scholar 

  6. Correia-Pinto J, Henriques-Coelho T, Roncon-Albuquerque R Jr, Lourenco AP, Melo-Rocha G, Vasques-Novoa F, Gillebert TC, Leite-Moreira AF (2009) Time course and mechanisms of left ventricular systolic and diastolic dysfunction in monocrotaline-induced pulmonary hypertension. Basic Res Cardiol 104:535–545

    Article  PubMed  Google Scholar 

  7. Epstein JA, Parmacek MS (2005) Recent advances in cardiac development with therapeutic implications for adult cardiovascular disease. Circulation 112:592–597

    Article  PubMed  Google Scholar 

  8. Falcao-Pires I, Goncalves N, Henriques-Coelho T, Moreira-Goncalves D, Roncon-Albuquerque R Jr, Leite-Moreira AF (2009) Apelin decreases myocardial injury and improves right ventricular function in monocrotaline-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 296:H2007–H2014

    Article  CAS  PubMed  Google Scholar 

  9. Frank L, Bucher JR, Roberts RJ (1978) Oxygen toxicity in neonatal and adult animals of various species. J Appl Physiol 45:699–704

    CAS  PubMed  Google Scholar 

  10. Fujii A, Rabinovitch M, Matthews EC (1981) A case of spontaneous resolution of idiopathic pulmonary hypertension. Br Heart J 46:574–577

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Garciarena CD, Pinilla OA, Nolly MB, Laguens RP, Escudero EM, Cingolani HE, Ennis IL (2009) Endurance training in the spontaneously hypertensive rat: conversion of pathological into physiological cardiac hypertrophy. Hypertension 53:708–714

    Article  CAS  PubMed  Google Scholar 

  12. Henriques-Coelho T, Correia-Pinto J, Roncon-Albuquerque R Jr, Baptista MJ, Lourenco AP, Oliveira SM, Brandao-Nogueira A, Teles A, Fortunato JM, Leite-Moreira AF (2004) Endogenous production of ghrelin and beneficial effects of its exogenous administration in monocrotaline-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 287:H2885–H2890

    Article  CAS  PubMed  Google Scholar 

  13. Ismat FA, Zhang M, Kook H, Huang B, Zhou R, Ferrari VA, Epstein JA, Patel VV (2005) Homeobox protein Hop functions in the adult cardiac conduction system. Circ Res 96:898–903

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Jasmin JF, Lucas M, Cernacek P, Dupuis J (2001) Effectiveness of a nonselective ET(A/B) and a selective ET(A) antagonist in rats with monocrotaline-induced pulmonary hypertension. Circulation 103:314–318

    Article  CAS  PubMed  Google Scholar 

  15. Junqueira LC, Bignolas G, Brentani RR (1979) Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections. Histochem J 11:447–455

    Article  CAS  PubMed  Google Scholar 

  16. Kook H, Lepore JJ, Gitler AD, Lu MM, Yung WWM, Mackay J, Zhou R, Ferrari V, Gruber P, Epstein JA (2003) Cardiac hypertrophy and histone deacetylase-dependent transcriptional repression mediated by the atypical homeodomain protein Hop. J Clin Invest 112:863–871

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Lalich JJ, Merkow L (1961) Pulmonary arteritis produced in rat by feeding Crotalaria spectabilis. Lab Invest 10:744–750

    CAS  PubMed  Google Scholar 

  18. Laugwitz KL, Moretti A, Lam J, Gruber P, Chen Y, Woodard S, Lin LZ, Cai CL, Lu MM, Reth M, Platoshyn O, Yuan JX, Evans S, Chien KR (2005) Postnatal isl1 + cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433:647–653

    Article  CAS  PubMed  Google Scholar 

  19. Loscalzo J (1992) Endothelial dysfunction in pulmonary hypertension. N Engl J Med 327:117–119

    Article  CAS  PubMed  Google Scholar 

  20. Mattocks AR (1968) Toxicity of pyrrolizidine alkaloids. Nature 217:723–728

    Article  CAS  PubMed  Google Scholar 

  21. Miyauchi T, Yorikane R, Sakai S, Sakurai T, Okada M, Nishikibe M, Yano M, Yamaguchi I, Sugishita Y, Goto K (1993) Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension. Circ Res 73:887–897

    Article  CAS  PubMed  Google Scholar 

  22. Piepoli MF, Capucci A (2009) Cardiac regeneration by progenitor cells: what is it known as and what is it still to be known as? Cardiovasc Hematol Agents Med Chem 7:127–136

    Article  CAS  PubMed  Google Scholar 

  23. Rabinovitch M, Gamble WJ, Miettinen OS, Reid L (1981) Age and sex influence on pulmonary hypertension of chronic hypoxia and on recovery. Am J Physiol 240:H62–H72

    CAS  PubMed  Google Scholar 

  24. Rabinovitch M, Keane JF, Norwood WI, Castaneda AR, Reid L (1984) Vascular structure in lung tissue obtained at biopsy correlated with pulmonary hemodynamic findings after repair of congenital heart defects. Circulation 69:655–667

    Article  CAS  PubMed  Google Scholar 

  25. Reffelmann T, Kloner RA (2009) Intracoronary blood- or bone marrow-derived cell transplantation in patients with ischemic heart disease. Regen Med 4:709–719

    Article  PubMed  Google Scholar 

  26. Reid MJ, Lame MW, Morin D, Wilson DW, Segall HJ (1998) Involvement of cytochrome P450 3A in the metabolism and covalent binding of 14C-monocrotaline in rat liver microsomes. J Biochem Mol Toxicol 12:157–166

    Article  CAS  PubMed  Google Scholar 

  27. Rosenzweig EB, Barst RJ (2008) Pulmonary arterial hypertension in children: a medical update. Curr Opin Pediatr 20:288–293

    Article  PubMed  Google Scholar 

  28. Rosenzweig EB, Widlitz AC, Barst RJ (2004) Pulmonary arterial hypertension in children. Pediatr Pulmonol 38:2–22

    Article  PubMed  Google Scholar 

  29. Stamm C, Choi YH, Nasseri B, Hetzer R (2009) A heart full of stem cells: the spectrum of myocardial progenitor cells in the postnatal heart. Ther Adv Cardiovasc Dis 3:215–229

    Article  PubMed  Google Scholar 

  30. Su X, Brower G, Janicki JS, Chen YF, Oparil S, Dell’Italia LJ (1999) Differential expression of natriuretic peptides and their receptors in volume overload cardiac hypertrophy in the rat. J Mol Cell Cardiol 31:1927–1936

    Article  CAS  PubMed  Google Scholar 

  31. Tatebe S, Miyamura H, Sugawara M, Watanabe H, Eguchi S (1996) Induction of right ventricular hypertrophy in neonatal guinea pigs by monocrotaline. Jpn Circ J 60:604–608

    Article  CAS  PubMed  Google Scholar 

  32. Todd L, Mullen M, Olley PM, Rabinovitch M (1985) Pulmonary toxicity of monocrotaline differs at critical periods of lung development. Pediatr Res 19:731–737

    Article  CAS  PubMed  Google Scholar 

  33. Ueno M, Miyauchi T, Sakai S, Kobayashi T, Goto K, Yamaguchi I (1999) Effects of physiological or pathological pressure load in vivo on myocardial expression of ET-1 and receptors. Am J Physiol 277:R1321–R1330

    CAS  PubMed  Google Scholar 

  34. Zuo XR, Wang Q, Cao Q, Yu YZ, Wang H, Bi LQ, Xie WP, Wang H (2012) Nicorandil prevents right ventricular remodeling by inhibiting apoptosis and lowering pressure overload in rats with pulmonary arterial hypertension. PLoS One 7:e44485

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Antónia Teles, Marta Oliveira, and Rosa Gonçalves for their invaluable technical assistance in this study.

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Authors and Affiliations

  1. Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Al. Prof Hernâni Monteiro, 4200-319, Porto, Portugal

    Marina Dias-Neto, Ana Luísa-Neves, Sónia Pinho, Nádia Gonçalves, Maria Mendes, Daniel Gonçalves, Manuel Ferreira-Pinto, Adelino F. Leite-Moreira & Tiago Henriques-Coelho

  2. Institute of Molecular Pathology and Immunology, University of Porto, R. Dr. Roberto Frias, 4200-465, Porto, Portugal

    Catarina Eloy & José M. Lopes

Authors
  1. Marina Dias-Neto
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  2. Ana Luísa-Neves
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  3. Sónia Pinho
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  4. Nádia Gonçalves
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  5. Maria Mendes
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  9. Manuel Ferreira-Pinto
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  10. Adelino F. Leite-Moreira
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  11. Tiago Henriques-Coelho
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Correspondence to Marina Dias-Neto.

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Dias-Neto, M., Luísa-Neves, A., Pinho, S. et al. Pathophysiology of Infantile Pulmonary Arterial Hypertension Induced by Monocrotaline. Pediatr Cardiol 36, 1000–1013 (2015). https://doi.org/10.1007/s00246-015-1111-y

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  • DOI: https://doi.org/10.1007/s00246-015-1111-y

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