online ISSN 2415-3176
print ISSN 1609-6371
logoExperimental and Clinical Physiology and Biochemistry
  • 14 of 16
ECPB 2015, 71(3): 84–90
Literature review

Monocrotaline induced pulmonary hypertension: mechanisms of development


Pulmonary hypertension (PH) develops as a result of the remodeling the pulmonary vasculature and is characterized by abnormal expansion of endothelial cells, medial hypertrophy, and adventitial thickening of pulmonary arteries, leading to obliteration of the arterial lumen, progressive right ventricular hypertrophy and eventually cardiac failure and death. Although any form of PH can contribute to the increased morbidity and mortality, pulmonary arterial hypertension (group 1) is particularly severe and progressive form with dismal prognosis. In the study of PAH pathobiology experimental animal models played a great role. The rat model of PH which is induced with the single subcutaneous/intraperitoneal injection of monocrotaline (MCT) has become popular in the general practice due to its high reproducibility, technical simplicity and low cost.

The article presents modern approaches to the understanding of the mechanisms involved into the development of monocrotaline induced pulmonary hypertension. MCT is naturally occurring pyrrolizidine alkaloid found in plant genus Crotalaria. Upon administration it undergoes biotransformation to reactive pyrrole (dehydromonocrotaline, DMCT) which exerts toxic effects on pulmonary circulation and liver. Progressive endothelial injury is speculated to trigger maladaptive remodeling of the pulmonary circulation with the abnormalities in nitric oxide signaling being shown to occur before the onset of PAH. Abnormal expression of vesicular transport proteins as well as bone morphogenetic protein type II receptor and endothelial nitric oxide synthase was noted during PAH development. Disruption of caveolae with a progressive loss of cav-1, which is involved in regulation of the inflammatory response, cell proliferation and apoptosis and inhibits number of mitogens implicated in PAH was suggested to be closely related to the MCT toxicity. Imbalance between apoptosis of endothelial cells and proliferation of pulmonary artery smooth muscle cells is a typical finding in MCT model of PH, which is currently attributed to the cav-1 associated activation of ERK1/2 signaling pathway with down-regulation of the bone morphogenetic protein signaling.

The inflammatory response in MCT model is caused not only by abnormalities in the cav-1 expression but also to activation of the systemic and pulmonary inflammatory response. Accumulation of the bone marrow derived macrophages and dendritic cells were detected in perivascular lesions both in PAH patients and MCT animals suggesting the pivotal role of the monocyte/macrophage activation for the pulmonary vascular remodeling. Altered inflammatory fibroblast phenotype is attributed to the epigenetic alteration, namely, increased catalytic activity and protein expression of class I histone acetyltransferases and histone deacetylases (HDACs). In turn, HDAC activity is significantly influenced by the pro-antioxidant balance in cells, pointing to the important role of oxidant status and oxidative stress in the development of monocrotaline induced PH. These assumptions were further corroborated by the findings that NLRP3 inflammasome is markedly up-regulated in MCT rats. Another important mechanism of action of MCT is formation of proteins and DNA adducts inducing cell cycle arrest and cell death.

MCT model of PH largely capture many of the cardinal features of the human disease such as endothelial cell damage, medial hypertrophy of the small pulmonary arteries, vascular inflammation, right ventricular hypertrophy. The pathogenetic similarities between monocrotaline-induced and human idiopathic pulmonary hypertension are discussed.

Keywords: pulmonary hypertension, pulmonary arterial hypertension, monocrotaline, inflammation, mechanisms

Full text: PDF (Ukr) 0.96M

  1. 1. Konopliova L, Kovalenko V, Amosova K et al. Diagnostics and treatment of pulmonary hypertension. Recommendations of the working group on the pulmonary hypertension. Ukrainian Journal of Cardiology. 2014;3:3-40.
  2. 2. Semen Kh. Modern approaches to the management of pulmonary arterial hypertension: focus on the upfront combination therapy and right ventricular dysfunction. Medyzyna transportu Ukrainy. 2014;4:64-70.
  3. 3. Buermans H, Redout E, Schiel А et al. Microarray analysis reveals pivotal divergent mRNA expression profiles early in the development of either compensated ventricular hypertrophy or heart failure. Physiological genomics. 2005;21(3):314-323.
  4. 4. DeLeve L, McCuskey R, Wang X et al. Characterization of a reproducible rat model of hepatic venoocclusive disease. Hepatology. 1999;29:1779-1791.
  5. 5. Deng Z, Morse J, Slager S et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000;67(3):737-744.
  6. 6. Edgar J, Molyneux R, Colegate S. Pyrrolizidine Alkaloids: Potential Role in the Etiology of Cancers, Pulmonary Hypertension, Congenital Anomalies and Liver Disease. Chemical research in toxicology. 2015;28(1):4-20.
  7. 7. Ezzat T, Van den Broek М, Davies N et al. The flavonoid monoHER prevents monocrotaline-induced hepatic sinusoidal injury in rats. J Surg Oncol. 2012;106(1):72-78.
  8. 8. Gilruth J. Hepatic cirrhosis affecting horses and cattle (so-called "Winton disease"). Wellington, New Zealand Department of Agriculture. 1903;228-279.
  9. 9. Gomez-Arroyo J, Farkas L, Alhussaini A et al. The monocrotaline model of pulmonary hypertension in perspective. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2012;302(4):363-369.
  10. 10. Haga S, Tsuchiya H, Hirai T et al. A novel ACE2 activator reduces monocrotaline-induced pulmonary hypertension by suppressing the JAK/STAT and TGF-β cascades with restored caveolin-1 expression. Exp Lung Res. 2015;41:21-31.
  11. 11. Huang J, Wolk H, Gewitz M et al. Progressive endothelial cell damage in an inflammatory model of pulmonary hypertension. Experimental lung research. 2010;36(1):57-66.
  12. 12. Huxtable R. Activation and pulmonary toxicity of pyrrolizidine alkaloids. Pharmacology & therapeutics. 1990;47(3):371-389.
  13. 13. Kay J, Harris P, Heath D. Pulmonary hypertension produced in rats by ingestion of Crotalaria spectabilis seeds. Thorax 22.2. 1967;176-179.
  14. 14. Kolettis T, Vlahos A, Louka M et al. Characterisation of a rat model of pulmonary arterial hypertension. Hellenic J Cardiol. 2007;48(4):206-210.
  15. 15. Li M, Riddle S, Frid M et al. Emergence of fibroblasts with proinflammatory epigenetically altered phyenotype in severe hypoxic pulmonary hypertension. J Immunol. 2011;187(5):2711-2272.
  16. 16. Мartinon F. Signaling by ROS drive inflammasome activation. Eur. J. Immunol. 2010;40:616-619.
  17. 17. Mathew R. Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity. Am J Physiol Heart Circ Physiol. 2014;306:15-25.
  18. 18. Morty R, Nejman B, Kwapiszewska G et al. Dysregulated bone morphogenetic protein signaling in monocrotaline-induced pulmonary arterial hypertension Arterioscler Thromb Vasc Biol. 2007;27(5):1072-1078.
  19. 19. Mukhopadhyay S, Shah M, Patel K et al. Monocrotaline pyrrole-induced megalocytosis of lung and breast epithelial cells: disruption of plasma membrane and Golgi dynamics and an enhanced unfolded protein response. Toxicology and applied pharmacology. 2006;21(3):209-220.
  20. 20. Nakayama Wong L, Lamé M, Jones A et al. Differential cellular responses to protein adducts of naphthoquinone and monocrotaline pyrrole. Chemical research in toxicology. 2010;23(9):1504-1513.
  21. 21. Niu Y, DesMarais T, Tong Z et al. Oxidative stress alters global histone modification and DNA methylation. Free Radic Biol Med. 2015;82:22-28.
  22. 22. Pan L, Lamé M, Morin D et al. Red blood cells augment transport of reactive metabolites of monocrotaline from liver to lung in isolated and tandem liver and lung preparations. Toxicology and applied pharmacology. 1991;110(2):336-346.
  23. 23. Perros F, Dorfmüller P, Souza R et al. Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension. Eur Respir J. 2007;29(3):462-468.
  24. 24. Price L, Wort S, Perros F et al. Inflammation in pulmonary arterial hypertension. CHEST Journal. 2012;141(1):210-221.
  25. 25. Ramos M, Lamé M, Segall H et al. Smad signaling in the rat model of monocrotaline pulmonary hypertension. Toxicol Pathol. 2008;36(2):311-20.
  26. 26. Reid M, Lame M, Morin D et al. Involvement of cytochrome P450 3A in the metabolism and covalent binding of 14C‐monocrotaline in rat liver microsomes. Journal of biochemical and molecular toxicology. 1998;12(3):157-166.<157::AID-JBT4>3.0.CO;2-K
  27. 27. Roitman J.N. Ingestion of pyrrolizidine alkaloids: a health hazard of global proportions . In: Finlay J.W., Schwass D.E. ed. Xenobiotics in foods and feeds, Washington DC, American Chemical Society. 1983. 345-378.
  28. 28. Roth R, Reindel J. Lung vascular injury from monocrotaline pyrrole, a putative hepatic metabolit. In Biological Reactive Intermediates IV. Springer New York. 1991. 477-487.
  29. 29. Schultze A, Roth R. Chronic pulmonary hypertension‐the monocrotaline model and involvement of the hemostatic system. Journal of Toxicology and Environmental Health, Part B Critical Reviews. 1998;1(4):271-346.
  30. 30. Stenmark K, Meyrick B, Galie N et al. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure American Journal of Physiology-Lung Cellular and Molecular Physiology. 2009;297(6):1013-1032.
  31. 31. Stenmark K, Yeager M, El Kasmi K et al. The adventitia: essential regulator of vascular wall structure and function. Annual review of physiology. 2013;75:23.
  32. 32. Tang B, Chen G,Y. Liang M et al. Ellagic acid prevents monocrotaline-induced pulmonary artery hypertension via inhibiting NLRP3 inflammasome activation in rats. International journal of cardiology. 2014;180:134-141.
  33. 33. Wilson D, Segall H, Pan L et al. Mechanisms and pathology of monocrotaline pulmonary toxicity. CRC Critical Reviews in Toxicology. 1992;22(5-6):307-325.
  34. 34. Woods L. Manipulation of injury and repair of the alveolar epithelium using two pneumotoxicants: 3-methylindole and monocrotaline. Experimental lung research. 1999;25(2):165-181.
  35. 35. Xi X, Liu S, Shi H et al. Serum–Glucocorticoid regulated kinase 1 regulates macrophage recruitment and activation contributing to monocrotaline-induced pulmonary аrterial hypertension. Cardiovascular toxicology. 2014;14(4):368-378.
  36. 36. Yang X, Long L, Southwood M et al. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circulation research. 2005;96:1053-1063.
  37. 37. Zhang H, Luo Q, Liu Z et al. Abnormal expression of vesicular transport proteins in pulmonary arterial hypertension in monocrotaline-treated rats. Acta biochimica et biophysica Sinica. 2015;130:1-8.

Програмування -