Hypertension as a cardiovascular proliverative disorder

  • Denis deBlois
  • Sergei Orlov
  • Pavel Harnet
Part of the Basic Science for the Cardiologist book series (BASC, volume 5)


The balance between growth and apoptosis: a key determinant of cardiovascular structure. Cardiovascular hypertrophy is an important feature of hypertension (1). However, the mechanisms regulating cardiovascular mass remain poorly defined. Spontaneously hypertensive rats (SHR) are born with elevated cardiovascular mass and DNA content, indicating the influence of genetic factors (2). Hypertrophy also develops secondarily to an increase in mechanical load as in aortic coarctation, or to chronic endocrine stimulation with, e.g., angiotensin II (AngII) (3,4). Hypertrophy which is associated with increased DNA replication is less readily reversible than hypertrophy that is solely due to increased protein synthesis without de novo DNA synthesis. Thus, in the vascular wall, DNA content (due to SMC hyperplasia or polyploidy (5)) may be considered as a record of past episodes of vascular growth, contributing to the persistence of the hypertensive disease. The prevention or regression of cardiovascular hypertrophy is now considered a key therapeutic target in the reduction of hypertension-associated morbidity and mortality. Apoptosis is an ubiquitous and highly regulated form of programmed cell death that is involved in tissue morphogenesis and homeostasis as the essential counterpart of cell replication (6,7). In this context, the balance between cell growth and apoptosis is a potential determinant of cardiac structure during development, disease and therapy (8).


Cell Shrinkage Small Heat Shock Protein Recombinant Inbred Strain Cardiovascular Hypertrophy Increase Cardiomyocyte Apoptosis 
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  1. 1.
    Folkow, B. 1982. Physiological aspects of primary hypertension. Physiol Rev 62:347–504.PubMedGoogle Scholar
  2. 2.
    Walter, S. V. and P. Hamet. 1986. Enhanced DNA synthesis in heart and kidney of newborn spontaneously hypertensive rats. Hypertension 8:520–525.PubMedGoogle Scholar
  3. 3.
    Teiger, E., T. V. Dam, L. Richard, C. Wisnewsky, B. S. Tea, L. Gaboury, J. Tremblay, K. Schwartz, and P. Hamet. 1996. Apoptosis in pressure overload-induced heart hypertrophy in the rat. J Clin Invest 97:2891–2897.PubMedGoogle Scholar
  4. 4.
    Kim, S., K. Ohta, A. Hamaguchi, T. Yukimura, K. Miura, and H. Iwao. 1995. Angiotensin II induces cardiac phenotypic modulation and remodeling in vivo in rats. Hypertension 25:1252–1259.PubMedGoogle Scholar
  5. 5.
    Owens, G. K. 1989. Control of hypertrophic versus hyperplastic growth of vascular smooth muscle cells. Am J Physiol 257(6Pt2):H1755–H1765.PubMedGoogle Scholar
  6. 6.
    Kerr, J. F. R., A. H. Wyllie, and A. R. Currie. 1972. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257.PubMedGoogle Scholar
  7. 7.
    Thompson, G. B. 1995. Apoptosis in the pathogenesis and treatment of disease. Science 267:1456–1462.PubMedCrossRefGoogle Scholar
  8. 8.
    Hamet, P., D. deBlois, T.-V. Dam, L. Richard, E. Teiger, B.-S. Tea, S. N. Orlov, and J. Tremblay. 1996. Apoptosis and vascular wall remodeling in hypertension. Can J of Physiol & Pharmacol 74(7):850–861.CrossRefGoogle Scholar
  9. 9.
    Majno, G. and I. Joris. 1995. Apoptosis, oncosis and necrosis. An overview of cell death. Am J Pathol 146:3–15.PubMedGoogle Scholar
  10. 10.
    Champagne, M.-J., P. Dumas, M. R. Bennett, S. N. Orlov, P. Hamet, and J. Tremblay. 1998. HSPs expression selectively protects against heat shock protein-induced growth inhibition and necrosis but not apoptosis in vascular smooth muscle cells. Hypertension 33(3):906–913.Google Scholar
  11. 11.
    Kajstura, J., M. Mansukhani, W. Cheng, K. Reiss, S. Krajewski, J. C. Reed, F. Quaini, E. H. Sonnenblick, and P. Anversa. 1995. Programmed cell death and expression of the protooncogene bcl-2 in myocytes during postnatal maturation of the heart. Exp Cell Res 219:110–121.PubMedCrossRefGoogle Scholar
  12. 12.
    Cheng, W., B. Li, J. Kajstura, P. Li, M. S. Wolin, E. H. Sonnenblick, T. H. Hintze, G. Olivetti, and P. Anversa. 1995. Stretch-induced programmed myocyte cell death. J Clin Invest 96:2247–2259PubMedGoogle Scholar
  13. 13.
    Hadrava, V., J. Tremblay, and P. Hamet. 1989. Abnormalities in growth characteristics of aortic smooth muscle cells in spontaneously hypertensive rats. Hypertension 13:589–597.PubMedGoogle Scholar
  14. 14.
    Scott-Burden, T., T. J. Resink, U. Baur, M. Burgin, and F. R. Buhler. 1989. Epidermal growth factor responsiveness in smooth muscle cells from hypertensive and normotensive rats. Hypertension 13:295–304.PubMedGoogle Scholar
  15. 15.
    Paquet, J. L, M. Baudouin-Legros, P. Marche, and P. Meyer. 1989. Enhanced proliferating activity of cultured smooth muscle celts from SHR. Am J Hypertens 2:108–110.PubMedGoogle Scholar
  16. 16.
    Hamet, P. 1995. Proliferation and apoptosis in hypertension, Curr Opin Nephrol Hypertens 4:1–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Hamet, P., L. Richard, T.-V. Dam, E. Teiger, S. N. Orlov, L. Gaboury, F. Gossard, and J. Tremblay. 1995. Apoptosis in target organs of hypertension. Hypertension 26:642–648.PubMedGoogle Scholar
  18. 18.
    Cho, A., D. W. Courtman, and B. L. Langille. 1995. Apoptosis (programmed cell death) in arteries of the neonatal lamb. Circ Res 76:168–175.PubMedGoogle Scholar
  19. 19.
    Orlov, S. N., T. V. Dam, J. Tremblay, and P. Hamet. 1996. Apoptosis in vascular smooth muscle cells: Role of cell shrinkage. Biochem Biophys Res Commun 221:708–715.PubMedCrossRefGoogle Scholar
  20. 20.
    Klassen, N. V., P. R. Walker, C. K. Ross, J. Cygler, and B. Lach. 1993. Two-stage cell shrinkage and the OER for radiation-induced apoptosis of rat thymocytes. Intern J Rad Biol 64:571–581.Google Scholar
  21. 21.
    Bortner, C. D. and J. A. Cidlowski. 1996. Absence of volume regulatory mechanisms contributes to the rapid activation of apoptosis in thymocytes. Am J Physiol 271:C950–C961.PubMedGoogle Scholar
  22. 22.
    Wyllie, A. H. and R. G. Morris. 1982. Hormone-induced cell death. Purification ad properties of thymocytes undergoing apoptosis after glucocorticoid treatment. Am J Pathol 109:78–87.PubMedGoogle Scholar
  23. 23.
    Wesselborg, S. and D. Kabelitz. 1993. Activation-driven death of human T cell clones: time course kinetics of the induction of cell shrinkage, DNA fragmentation, and cell death. Cellular Immunology 148:234–241.PubMedCrossRefGoogle Scholar
  24. 24.
    Thomas, N. and P. A. Bell. 1981. Glucocorticoid-induced cell-size changes and nuclear fragility in rat thymocytes. Mol Cell Endocrinol 22:71–84.PubMedCrossRefGoogle Scholar
  25. 25.
    Beauvais, F., L. Michel, and L. Dubertret. 1995. Human eosinophils in culture undergo a striking and rapid shrinkage during apoptosis. J Leukocyte Biol 57:851–855.PubMedGoogle Scholar
  26. 26.
    Vaux, D. L., G. Haecker, and A. Strasser. 1994. An evolutionary perspective on apoptosis. Cell 76:777–779.PubMedCrossRefGoogle Scholar
  27. 27.
    Nicholson, D. W., A. Ali, N. A. Thornberry, J. P. Vaillancourt, C. K. King, M. Gallant, Y. Gareau, P. R. Friffin, M. Labelle, Y. A. Lazebnik, N. A. Munday, S. M. Raju, M. E. Smulson, T. T. Yamin, V. L. Yu, and D. K. Miller. 1995. Identification and inhibition of the ICE/CCED-3 protease necessary for mammalian apoptosis. Nature 376:37–43.PubMedCrossRefGoogle Scholar
  28. 28.
    Darmon, A. J., D. W. Nicholson, and R. C. Bleackley. 1995, Activation of the apoptotic protease CPP32 by cytotoxic cell-derived granzyme B. Nature 377:446–448.PubMedCrossRefGoogle Scholar
  29. 29.
    Schlegel, J., I. Peters, S. Orrenius, D. K. Miller, N. A. Thornberry, T. T. Yamin, and D. W. Nicholson. 1996. CPP32 apopain is a key interleukin 1-beta converting enzyme-like protease involved in Fas-mediated apoptosis. J Biol Chem 271:1841–1844.PubMedCrossRefGoogle Scholar
  30. 30.
    Qrth, K., K. O’Rourke, G. S. Salvesen, and V. M. Dixit. 1996. Molecular ordering of apoptotic mammalian CED-3/ICE-like proteases. J Biol Chem 271:20977–20980.CrossRefGoogle Scholar
  31. 31.
    Bortner, C. D., N. B. E. Oldenburg, and J. A. Cidlowski. 1995. The role of DNA fragmentation in apoptosis. Trends in Cell Biology 5:21–26.PubMedCrossRefGoogle Scholar
  32. 32.
    deBlois, D., B.-S. Tea, T.-V. Dam, J. Tremblay, and P. Hamet. 1997. Smooth muscle cell apoptosis during vascular regression in spontaneously hypertensive rats. Hypertension 29:340–349.PubMedGoogle Scholar
  33. 33.
    Diez, J., A. Panizo, M. Hernandez, and J. Pardo. 1997. Is the regulation of apoptosis altered in smooth muscle cells of adult spontaneously hypertensive rats? Hypertension 29:776–780.PubMedGoogle Scholar
  34. 34.
    Sharifi, A. M. and E. L. Schiffrin. 1997. Apoptosis in aorta of deoxycorticosterone acetate-salt hypertensive rats: effect of endothelin receptor antagonism. J Hypertens 15:1441–1448.PubMedCrossRefGoogle Scholar
  35. 35a.
    Diez, J., A. Panizo, M. Hernandez, F. Vega, I. Sola, M. A. Fortuno, and J. Pardo. 1997. Cardiomyocyte apoptosis and cardiac angiotensin-converting enzyme in spontaneously hypertensive rats. Hypertension 30:1029–1034.PubMedGoogle Scholar
  36. 35b.
    Fortuno, M. A., S. Ravassa, J. C. Etayo, and J. Diez. 1998. Overexpression of Bax protein and enhanced apoptosis in the left ventricle of spontaneously hypertensive rats: effects of ATI blockade with losartan. Hypertension 32:280–286.PubMedGoogle Scholar
  37. 35c.
    Tea B-S, Dam T-V, Moreau P, Hamet P, deBlois D, 1999. Apoptosis during regression of cardiac hypertrophy in spontaneously hypertensive rats: temporal regulation and spatial heterogeneity. Hypertension (In press)Google Scholar
  38. 36.
    Hamet, P., P. Moreau, T-V. Dam, S. N. Orlov, B-S. Tea, D. deBlois, and J. Tremblay. 1996. The time window of apoptosis: a new component in the therapeutic strategy for cardiovascular remodeling. J Hypertens 14(Suppl 5):S65–S70.Google Scholar
  39. 37.
    Schiffrin, E. L, L. Y. Deng, and P. Larochelle. 1994. Effects of a beta-blocker or a converting enzyme inhibitor on resistance arteries in essential hypertension. Hypertension 23:83–91.PubMedGoogle Scholar
  40. 38.
    Touyz, R. M, J. Fareh, G. Thibault, and E. L. Schiffrin. 1996. Intracellular Ca2+ modulation by angiotensin II and endothelin-1 in cardiomyocytes and fibroblasts from hypertrophied hearts of spontaneously hypertensive rats. Hypertension 28:797–805.PubMedGoogle Scholar
  41. 39.
    Brooks, W. W., O. H. Bing, K. G. Robinson, M. T. Slawsky, D. M. Chaletsky, and C. H. Conrad. 1997. Effect of angiotensin-converting enzyme inhibition on myocardial fibrosis and function in hypertrophied and failing myocardium from the spontaneously hypertensive rat (see comments). Circulation 96:4002–4010.PubMedGoogle Scholar
  42. 40.
    Li, Z., O. H. Bing, X. Long, K. G. Robinson, and E. G. Lakatta. 1997. Increased cardiomyocyte apoptosis during the transition to heart failure in the spontaneously hypertensive rat. Am J Physiol 272:H2313–H23I9.PubMedGoogle Scholar
  43. 41.
    Tomanek, R. J. and M. T. Whitaker. 1990. Compensated function in hypertrophied ventricles of Wistar Kyoto and spontaneously hypertensive rats. Cardiovasc Res 24:204–209.PubMedGoogle Scholar
  44. 42.
    Friberg, P. and M. A. Adams. 1990. Cardiac and vascular structural adaptation in experimental hypertension. Eur Heart J 11Suppl G:65–71.PubMedGoogle Scholar
  45. 43.
    Conrad, C. H., W. W. Brooks, K. G. Robinson, and O. H. Bing. 1991. Impaired myocardial function in spontaneously hypertensive rats with heart failure. Am J Physiol 260:H136–H145.PubMedGoogle Scholar
  46. 44.
    Bennett, M. R., G. I. Evan, and S. M. Schwartz. 1995. Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. J Clin Invest 95(5):2266–2274.PubMedGoogle Scholar
  47. 45.
    Hannun, Y. A. 1996. Functions of ceramide in coordinating cellular responses to stress. Science 274:1855–1859.PubMedCrossRefGoogle Scholar
  48. 46.
    Green, D. R., A. Mahboubi, W. Nishoka, F. Echeverri, Y. Shi, J. Glynn, Y. Yang, J. Ashwell, and R. Bissonnette. 1994. Promotion and inhibition og activation-induced apoptosis in T-cell hybridomas by oncogenes and related signals. Immunol Rev 142:321–342.PubMedCrossRefGoogle Scholar
  49. 47.
    Paulovicj, A. G., D. P. Toczyski, and H. L. Hartwell. 1997. When checkpoints fail. Cell 88:315–322.CrossRefGoogle Scholar
  50. 48.
    Hadrava, V., J. Tremblay, R. P. Sekaly, and P. Hamet. 1992. Accelerated entry of aortic smooth muscle cells from spontaneously hypertensive rats into the S phase of the cell cycle. Biochem Cell Biol 70:599–604.PubMedGoogle Scholar
  51. 49.
    Hamet, P., Y. L. Sun, J. Kunes, M Pravenec, V. Kren, and J. Tremblay. 1997. The persistance of rat neonatal phenotype of heart weight into adulthood is associated with Acaa locus on chromosome 8. Hypertension 30(3):485.(Abstr.)Google Scholar
  52. 50.
    Bennett, M. R., G. I. Evan, and A. C. Newby. 1994. Deregulated expression of the c-myc oncogene abolishes inhibition of proliferation of rat vascular smooth muscle cells by serum reduction, interferon-gamma, heparin, and cyclic nucleotide analogues and induces apoptosis. Circ Res 74:525–536.PubMedGoogle Scholar
  53. 51.
    Bennett, M. R., G. I. Evan, and S. M. Schwartz. 1995. Apoptosis of rat vascular smooth muscle cells is regulated by p53 dependent and independent pathways. Circ Res 77:266–273.PubMedGoogle Scholar
  54. 52.
    Nagata, S. 1997. Apoptosis by death factor. (Review) (85 refs). Cell 88:355–365.PubMedCrossRefGoogle Scholar
  55. 53.
    Vilcek, J. and T. H. Lee. 1991. Tumor necrosis factor. New insights into the molecular mechanisms of its multiple actions. (Review) (99 refs). J Biol Chem 266:7313–7316.PubMedGoogle Scholar
  56. 54.
    Hamet, P., D. Kong, M Pravenec, J. Kunes, V. Kren, P. Klir, Y. Sun, and J. Tremblay. 1992. Restriction fragment length polymorphism of hsp70 gene, localized in the RT1 complex, spontaneously hypertensive rats. J Hypertens 19:611–614.Google Scholar
  57. 56.
    Goodman, Y. and M. P. Mattson. 1996. Ceramide protects hippocampal neurons against excitotoxic and oxidative insults, and amyloid beta-peptide toxicity. J Neurochem 66:869–872.PubMedGoogle Scholar
  58. 57.
    Fernandez, A., M. C. Marin, T. McDonnell, and H. N. Ananthaswamy. 1994. Differential sensitivity of normal and Ha-ras-transformed C3H mouse embryo fibroblasts to tumor necrosis factor: induction of bcl-2, c-myc, and manganese Superoxide dismutase in resistant cells. Oncogene 9:2009–2017.PubMedGoogle Scholar
  59. 58.
    Park, E., C. I. Kalunta, T. T. Nguyen, C. L. Wang, F. S. Chen, C. K. Lin, J. S. Kaptein, and P. M. Lad. 1996. TNF-alpha inhibits anti-IgM-mediated apoptosis in Ramos cells. Exp Cell Res 226:1–10.PubMedCrossRefGoogle Scholar
  60. 59.
    Krown, K. A., M. T, Page, C. Nguyen, D. Zechner, V. Gutierrez, K. L. Comstock, C. C. Glembotski, P. J. Quintana, and R. A. Sabbadini. 1996. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest 98:2854–2865.PubMedGoogle Scholar
  61. 60.
    Kim, Y. M., M. E. de Vera, S. C. Watkins, and T. R. Billiar. 1997. Nitric oxide protects cultured rat hepatocytes from tumor necrosis factor-alpha-induced apoptosis by inducing heat shock protein 70 expression. J Biot Chem 272:1402–1411.CrossRefGoogle Scholar
  62. 61.
    Mehlen, P., K. Schulze-Osthoff, and A. P. Arrigo. 1996. Small stress proteins as novel regulators of apoptosis. Heat shock protein 27 blocks Fas/APO-1-and staurosporine-induced cell death. J Biol Chem 271:16510–16514.PubMedCrossRefGoogle Scholar
  63. 62.
    Harriet, P., M. A. Kaiser, Y. Sun, V. Page, M. Vincent, V. Kren, M. Pravenec, J. Kunes, J. Tremblay, and N. J. Samani. 1996. HSP27 locus cosegregates with left ventricular mass independently of blood pressure. Hypertension 28:1112–1117.Google Scholar
  64. 63.
    Pravenec, M., Y. L. Sun, J. Kunes, D. Kong, V. Kren, P. Klir, J. Tremblay, and P. Hamet. 1991. Environmenta suceptibility in hypertension: potential role of HSP70 and TNFalpha genes. J Vase Med Biol 3:297–302.Google Scholar
  65. 64.
    Hamet P., Pausova Z., Adarichev V., Adaricheva K., Tremblay J. 1996. Hypertension: genes and environment. J Hypertens 1998 Apr;16(4):397–418Google Scholar
  66. 65.
    Pausova Z., Tremblay J. and P. Hamet. 1999. Gene-environment interaction in hypertension. Curr Hypertens Report (In press).Google Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Denis deBlois
    • 1
  • Sergei Orlov
    • 1
  • Pavel Harnet
    • 1
  1. 1.University of Montreal HospitalMontrealCanada

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