Journal of Molecular Medicine

, Volume 91, Issue 11, pp 1315–1327 | Cite as

A metabolic remodeling in right ventricular hypertrophy is associated with decreased angiogenesis and a transition from a compensated to a decompensated state in pulmonary hypertension

  • Gopinath Sutendra
  • Peter Dromparis
  • Roxane Paulin
  • Sotirios Zervopoulos
  • Alois Haromy
  • Jayan Nagendran
  • Evangelos D. Michelakis
Original Article


Right ventricular (RV) failure is an important clinical problem with no available therapies, largely because its molecular mechanisms are unknown. Mitochondrial remodeling resulting to a metabolic shift toward glycolysis has been described in RV hypertrophy (RVH), but it is unknown whether this is beneficial or detrimental. While clinically RV failure follows a period of compensation, the transition from a compensated (cRVH) to a decompensated hypertrophied RV (dRVH) is not studied in animal models. We modeled the natural history of RVH and failure in the monocrotaline rat model of pulmonary hypertension by serially assessing clinically relevant parameters in the same animal. We defined dRVH as the stage in which RV systolic pressure started decreasing, along with the cardiac output, while the RV continued to remodel. dRVH was characterized by ascites, weight loss, and high mortality, compared to cRVH. A cRVH myocardium had hyperpolarized mitochondria and low production of mitochondria-derived reactive oxygen species (mROS), activated hypoxia-inducible factor 1α (HIF1α), and increased levels of glucose transporter 1, vascular endothelial growth factor, and stromal-derived factor 1, promoting increased glucose uptake (measured by positron emission tomography–computed tomography) and angiogenesis measured by lectin imaging in vivo. The transition to dRVH was marked by a sharp rise in mROS, inhibition of HIF1α, and activation of p53, both of which contributed to down-regulation of pyruvate dehydrogenase kinase and decreased glucose uptake. This transition was also associated with a sharp decrease in angiogenic factors and angiogenesis. We show that the previously described metabolic shift, promoting HIF1α activation and angiogenesis, is not sustained during the progression of RV failure. The loss of this beneficial remodeling may be triggered by a rise in mROS resulting in HIF1α inhibition and suppressed angiogenesis. The resultant ischemia may contribute to the rapid deterioration of RV function upon entrance to a decompensation phase. The use of clinical criteria and techniques to define and study dRVH facilitates clinical translation of our findings with direct implications for RV therapeutic and biomarker discovery programs.

Key message

  • Decreased RV angiogenesis marks the transition from a cRVH to a dRVH.

  • The RVs in cRVH animals are associated with decreased mROS and increased HIF1α activity compared to dRVH.

  • The RVs in cRVH animals have increased GLUT1 levels and increased glucose uptake compared to the dRVH.


Hypoxia-inducible factor 1α Angiogenesis Metabolism Right ventricular failure Ischemia 

Supplementary material

109_2013_1059_MOESM1_ESM.doc (763 kb)
ESM 1(DOC 763 kb) (273.2 mb)
Supplementary Videos 1–3Stereological representation of capillary networks in the right ventricle at a high magnification marked by lectin fluorescence (green) and the nuclear stain DAPI (blue) are shown. Also please refer to Fig. 6B for quantified mean data. Supplementary Video 1 is a stereological representation of the right ventricle of a baseline control animal, while Supplementary Video 2 is a stereological representation of the right ventricle of a cRVH animal and Supplementary Video 3 is a stereological representation of the right ventricle of a dRVH animal. (MOV 279722 kb) (273.2 mb)
Supplementary Video 2(MOV 279722 kb) (273.7 mb)
Supplementary Video 3(MOV 280262 kb)


  1. 1.
    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 135:794–804PubMedCrossRefGoogle Scholar
  2. 2.
    Haddad F, Ashley E, Michelakis ED (2010) New insights for the diagnosis and management of right ventricular failure, from molecular imaging to targeted right ventricular therapy. Curr Opin Cardiol 25:131–140PubMedGoogle Scholar
  3. 3.
    Haddad F, Hunt SA, Rosenthal DN, Murphy DJ (2008) Right ventricular function in cardiovascular disease, part I: anatomy, physiology, aging, and functional assessment of the right ventricle. Circulation 117:1436–1448PubMedCrossRefGoogle Scholar
  4. 4.
    Haddad F, Doyle R, Murphy DJ, Hunt SA (2008) Right ventricular function in cardiovascular disease, part II: pathophysiology, clinical importance, and management of right ventricular failure. Circulation 117:1717–1731PubMedCrossRefGoogle Scholar
  5. 5.
    McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, Ahearn G (2004) Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 126:78S–92SPubMedCrossRefGoogle Scholar
  6. 6.
    Bogaard HJ, Natarajan R, Henderson SC, Long CS, Kraskauskas D, Smithson L, Ockaili R, McCord JM, Voelkel NF (2009) Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure. Circulation 120:1951–1960PubMedCrossRefGoogle Scholar
  7. 7.
    van de Veerdonk MC, Kind T, Marcus JT, Mauritz GJ, Heymans MW, Bogaard HJ, Boonstra A, Marques KM, Westerhof N, Vonk-Noordegraaf A (2011) Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol 58:2511–2519PubMedCrossRefGoogle Scholar
  8. 8.
    Srivastava D (2006) Making or breaking the heart: from lineage determination to morphogenesis. Cell 126:1037–1048PubMedCrossRefGoogle Scholar
  9. 9.
    Bishop SP, Altschuld RA (1970) Increased glycolytic metabolism in cardiac hypertrophy and congestive failure. Am J Physiol 218:153–159PubMedGoogle Scholar
  10. 10.
    Piao L, Fang YH, Cadete VJ, Wietholt C, Urboniene D, Toth PT, Marsboom G, Zhang HJ, Haber I, Rehman J et al (2010) The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle. J Mol Med 88:47–60PubMedCrossRefGoogle Scholar
  11. 11.
    Gomez A, Bialostozky D, Zajarias A, Santos E, Palomar A, Martinez ML, Sandoval J (2001) Right ventricular ischemia in patients with primary pulmonary hypertension. J Am Coll Cardiol 38:1137–1142PubMedCrossRefGoogle Scholar
  12. 12.
    Sutendra G, Dromparis P, Kinnaird A, Stenson TH, Haromy A, Parker JM, McMurtry MS, Michelakis ED (2013) Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer. Oncogene 32:1638–1650PubMedCrossRefGoogle Scholar
  13. 13.
    Bruel A, Oxlund H, Nyengaard JR (2005) The total length of myocytes and capillaries, and total number of myocyte nuclei in the rat heart are time-dependently increased by growth hormone. Growth Horm IGF Res 15:256–264PubMedCrossRefGoogle Scholar
  14. 14.
    Sutendra G, Dromparis P, Bonnet S, Haromy A, McMurtry MS, Bleackley RC, Michelakis ED (2011) Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFalpha contributes to the pathogenesis of pulmonary arterial hypertension. J Mol Med (Berl) 89:771–783CrossRefGoogle Scholar
  15. 15.
    Sutendra G, Dromparis P, Wright P, Bonnet S, Haromy A, Hao Z, McMurtry MS, Michalak M, Vance JE, Sessa WC et al (2011) The role of Nogo and the mitochondria-endoplasmic reticulum unit in pulmonary hypertension. Sci Transl Med 3:88ra55PubMedCrossRefGoogle Scholar
  16. 16.
    Ceconi C, Condorelli E, Quinzanini M, Rodella A, Ferrari R, Harris P (1989) Noradrenaline, atrial natriuretic peptide, bombesin and neurotensin in myocardium and blood of rats in congestive cardiac failure. Cardiovasc Res 23:674–682PubMedCrossRefGoogle Scholar
  17. 17.
    Muders F, Elsner D (2000) Animal models of chronic heart failure. Pharmacol Res 41:605–612PubMedCrossRefGoogle Scholar
  18. 18.
    Gomez-Arroyo JG, Farkas L, Alhussaini AA, Farkas D, Kraskauskas D, Voelkel NF, Bogaard HJ (2012) The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Lung Cell Mol Physiol 302:L363–L369PubMedCrossRefGoogle Scholar
  19. 19.
    Nagendran J, Gurtu V, Fu DZ, Dyck JR, Haromy A, Ross DB, Rebeyka IM, Michelakis ED (2008) A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted. J Thorac Cardiovasc Surg 136:168–178, 178 e161-163PubMedCrossRefGoogle Scholar
  20. 20.
    Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Harry G et al (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11:37–51PubMedCrossRefGoogle Scholar
  21. 21.
    Sutendra G, Bonnet S, Rochefort G, Haromy A, Folmes KD, Lopaschuk GD, Dyck JR, Michelakis ED (2010) Fatty acid oxidation and malonyl-CoA decarboxylase in the vascular remodeling of pulmonary hypertension. Sci Transl Med 2:44ra58PubMedCrossRefGoogle Scholar
  22. 22.
    Dromparis P, Sutendra G, Michelakis ED (2010) The role of mitochondria in pulmonary vascular remodeling. J Mol Med (Berl) 88:1003–1010CrossRefGoogle Scholar
  23. 23.
    Oikawa M, Kagaya Y, Otani H, Sakuma M, Demachi J, Suzuki J, Takahashi T, Nawata J, Ido T, Watanabe J et al (2005) Increased [18F]fluorodeoxyglucose accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenol. J Am Coll Cardiol 45:1849–1855PubMedCrossRefGoogle Scholar
  24. 24.
    Huang LE, Arany Z, Livingston DM, Bunn HF (1996) Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. J Biol Chem 271:32253–32259PubMedCrossRefGoogle Scholar
  25. 25.
    Salceda S, Caro J (1997) Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 272:22642–22647PubMedCrossRefGoogle Scholar
  26. 26.
    Wang GL, Jiang BH, Semenza GL (1995) Effect of altered redox states on expression and DNA-binding activity of hypoxia-inducible factor 1. Biochem Biophys Res Commun 212:550–556PubMedCrossRefGoogle Scholar
  27. 27.
    Brunelle JK, Bell EL, Quesada NM, Vercauteren K, Tiranti V, Zeviani M, Scarpulla RC, Chandel NS (2005) Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell Metab 1:409–414PubMedCrossRefGoogle Scholar
  28. 28.
    Denko NC (2008) Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 8:705–713PubMedCrossRefGoogle Scholar
  29. 29.
    Mansfield KD, Guzy RD, Pan Y, Young RM, Cash TP, Schumacker PT, Simon MC (2005) Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metab 1:393–399PubMedCrossRefGoogle Scholar
  30. 30.
    MacKenzie ED, Selak MA, Tennant DA, Payne LJ, Crosby S, Frederiksen CM, Watson DG, Gottlieb E (2007) Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Mol Cell Biol 27:3282–3289PubMedCrossRefGoogle Scholar
  31. 31.
    Huang C, Zhang Z, Ding M, Li J, Ye J, Leonard SS, Shen HM, Butterworth L, Lu Y, Costa M et al (2000) Vanadate induces p53 transactivation through hydrogen peroxide and causes apoptosis. J Biol Chem 275:32516–32522PubMedCrossRefGoogle Scholar
  32. 32.
    Wang S, Leonard SS, Ye J, Ding M, Shi X (2000) The role of hydroxyl radical as a messenger in Cr(VI)-induced p53 activation. Am J Physiol Cell Physiol 279:C868–C875PubMedGoogle Scholar
  33. 33.
    Xie S, Wang Q, Wu H, Cogswell J, Lu L, Jhanwar-Uniyal M, Dai W (2001) Reactive oxygen species-induced phosphorylation of p53 on serine 20 is mediated in part by polo-like kinase-3. J Biol Chem 276:36194–36199PubMedCrossRefGoogle Scholar
  34. 34.
    Watcharasit P, Bijur GN, Song L, Zhu J, Chen X, Jope RS (2003) Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53. J Biol Chem 278:48872–48879PubMedCrossRefGoogle Scholar
  35. 35.
    Schmid T, Zhou J, Kohl R, Brune B (2004) p300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1). Biochem J 380:289–295PubMedCrossRefGoogle Scholar
  36. 36.
    Vousden KH, Ryan KM (2009) p53 and metabolism. Nat Rev Cancer 9:691–700PubMedCrossRefGoogle Scholar
  37. 37.
    Kaluzova M, Kaluz S, Lerman MI, Stanbridge EJ (2004) DNA damage is a prerequisite for p53-mediated proteasomal degradation of HIF-1alpha in hypoxic cells and downregulation of the hypoxia marker carbonic anhydrase IX. Mol Cell Biol 24:5757–5766PubMedCrossRefGoogle Scholar
  38. 38.
    Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, Dillehay LE, Madan A, Semenza GL, Bedi A (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 14:34–44PubMedGoogle Scholar
  39. 39.
    Gudi R, Bowker-Kinley MM, Kedishvili NY, Zhao Y, Popov KM (1995) Diversity of the pyruvate dehydrogenase kinase gene family in humans. J Biol Chem 270:28989–28994PubMedCrossRefGoogle Scholar
  40. 40.
    Gomez-Arroyo J, Mizuno S, Szczepanek K, Van Tassell B, Natarajan R, dos Remedios CG, Drake JI, Farkas L, Kraskauskas D, Wijesinghe DS et al (2012) Metabolic gene remodeling and mitochondrial dysfunction in failing right ventricular hypertrophy secondary to pulmonary arterial hypertension. Circ Heart Fail 6:136–144PubMedCrossRefGoogle Scholar
  41. 41.
    Lundgrin EL, Park MM, Sharp J, Tang WH, Thomas JD, Asosingh K, Comhair SA, Difilippo FP, Neumann DR, Davis L et al (2013) Fasting 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography to detect metabolic changes in pulmonary arterial hypertension hearts over 1 year. Ann Am Thorac Soc 10:1–9PubMedGoogle Scholar
  42. 42.
    Bogaard HJ, Natarajan R, Mizuno S, Abbate A, Chang PJ, Chau VQ, Hoke NN, Kraskauskas D, Kasper M, Salloum FN et al (2010) Adrenergic receptor blockade reverses right heart remodeling and dysfunction in pulmonary hypertensive rats. Am J Respir Crit Care Med 182:652–660PubMedCrossRefGoogle Scholar
  43. 43.
    Yasunari K, Maeda K, Nakamura M, Yoshikawa J (2002) Carvedilol inhibits pressure-induced increase in oxidative stress in coronary smooth muscle cells. Hypertens Res 25:419–425PubMedCrossRefGoogle Scholar
  44. 44.
    Nakamura K, Kusano K, Nakamura Y, Kakishita M, Ohta K, Nagase S, Yamamoto M, Miyaji K, Saito H, Morita H et al (2002) Carvedilol decreases elevated oxidative stress in human failing myocardium. Circulation 105:2867–2871PubMedCrossRefGoogle Scholar
  45. 45.
    Sano M, Minamino T, Toko H, Miyauchi H, Orimo M, Qin Y, Akazawa H, Tateno K, Kayama Y, Harada M et al (2007) p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature 446:444–448PubMedCrossRefGoogle Scholar
  46. 46.
    Song H, Conte JV Jr, Foster AH, McLaughlin JS, Wei C (1999) Increased p53 protein expression in human failing myocardium. J Heart Lung Transplant 18:744–749PubMedCrossRefGoogle Scholar
  47. 47.
    Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB (2009) ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324:1076–1080PubMedCrossRefGoogle Scholar
  48. 48.
    Tang Y, Zhao W, Chen Y, Zhao Y, Gu W (2008) Acetylation is indispensable for p53 activation. Cell 133:612–626PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Gopinath Sutendra
    • 1
  • Peter Dromparis
    • 1
  • Roxane Paulin
    • 1
  • Sotirios Zervopoulos
    • 1
  • Alois Haromy
    • 1
  • Jayan Nagendran
    • 2
  • Evangelos D. Michelakis
    • 1
  1. 1.Department of MedicineUniversity of AlbertaEdmontonCanada
  2. 2.Department of SurgeryUniversity of AlbertaEdmontonCanada

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