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Mutant Animal Models of Stroke and Gene Expression

The Stroke-Prone Spontaneously Hypertensive Rat
  • Hilary V. O. Carswell
  • Martin W. McBride
  • Delyth Graham
  • Anna F. Dominiczak
  • I. Mhairi Macrae
Part of the Methods in Molecular Medicine book series (MIMM, volume 104)

Abstract

The recent completion of the Human Genome Project provides the potential to advance our knowledge of pathogenesis and identify the gene(s) associated with particular diseases. However, using human DNA to correlate individual genomic variations with particular disorders such as stroke will be extremely challenging because of the large number of variables within an individual, and across different populations. Mutant animal models of stroke such as the stroke-prone spontaneously hypertensive rat (SHRSP) provide the scientist with genetic homogeneity, not possible within a human population, to aid our search for causative genes. This chapter describes the methods our group have employed to study the genetic heritability of stroke sensitivity in the SHRSP. Sections are included on quantitative trait loci, mapping, and congenic strain construction for the identification of genetic determinants of stroke sensitivity in the SHRSP.

Key Words

Genotyping polymerase chain reaction microsatellite markers quantitative trait locus (QTL) genetic mapping congenic middle cerebral artery occlusion infarct volume 

References

  1. 1.
    Kidwell, C. S., Liebeskind, D. S., Starkman, S., and Saver, J. L. (2001) Trends in acute ischemic stroke trials through the 20th century. Stroke 32, 1349–1359.PubMedGoogle Scholar
  2. 2.
    Brass, L. M., Isaacsohn, J. L., Merikangas, K. R., Robinette, C. D. (1992) rA study of twins and stroke. Stroke 23, 221–223.PubMedGoogle Scholar
  3. 3.
    Kiely, D. K., Wolf, P. A., Cupples, L. A., Beiser, A. S., Myers, R. H. (1993) Familial aggregation of stroke. The Framingham Study. Stroke 24, 1366–1371.PubMedGoogle Scholar
  4. 4.
    Graffagnino, C, Gasecki, A. P., Doig, G. S., Hachinski, V. C. (1994) The importance of family history in cerebrovascular disease. Stroke 25, 1599–1604.PubMedGoogle Scholar
  5. 5.
    Diaz, J. F., Hachinski, V. C, Pederson, L. L., Donald, A. (1986) Aggregation of multiple risk factors for stroke in siblings of patients with brain infarction and transient ischemic attacks. Stroke 17, 1239–1242.PubMedGoogle Scholar
  6. 6.
    Joutel, A., Corpechot, C, Ducros, A., et al. (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 24, 707–110.CrossRefGoogle Scholar
  7. 7.
    Palsdottir, A., Abrahamson, M., Thorsteinsson, L., et al. (1988) Mutation in cystatin C gene causes hereditary brain haemorrhage. Lancet 2, 603–604.PubMedCrossRefGoogle Scholar
  8. 8.
    Levy, E., Carman, M. D., Fernandez-Madrid, I. J., et al. (1990) Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248, 1124–1126.PubMedCrossRefGoogle Scholar
  9. 9.
    Laberge-le Couteulx, S., Jung, H. H., Labauge, P., et al. (1999) Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat. Genet. 23, 189–193.PubMedCrossRefGoogle Scholar
  10. 10.
    Sahoo, T., Johnson, E. W., Thomas, J. W., et al. (1999) Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum. Mol. Genet. 8, 2325–2333.PubMedCrossRefGoogle Scholar
  11. 11.
    Alberts, M. J. (2001) Genetic update. Impact of the human genome projects and identification of a stroke gene. Stroke 32, 1239–1241.PubMedGoogle Scholar
  12. 12.
    Gretarsdottir, S., Sveinbjornsdottir, S., Jonsson, H.H., et al. (2002) Localization of a susceptibility gene for common forms of stroke to 5q12. Am. J. Hum. Genet. 70, 593–603.PubMedCrossRefGoogle Scholar
  13. 13.
    Yamori, Y., Horie, R., Handa, H., Sato, M., Fukase, M. (1976) Pathogenetic similarity of strokes in stroke-prone spontaneously hypertensive rats and humans. Stroke 7, 46–53.PubMedGoogle Scholar
  14. 14.
    Okamoto, K., Yamori, Y., and Nagaoka, A. (1974) Establishment of the SHRSPs (SHR). Circ. Res. 34(suppl. I), I143–I153Google Scholar
  15. 15.
    Coyle, P. and Jokelainen, P. T. (1983) Differential outcome to middle cerebral artery occlusion in spontaneously hypertensive stroke-prone rats (SHRSP) and Wistar Kyoto (WKY) rats. Stroke 14, 605–611.PubMedGoogle Scholar
  16. 16.
    Jeffs, B., Clark, J. S., Anderson, N. H., et al. (1997) Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus. Nat. Genet. 16, 364–367.PubMedCrossRefGoogle Scholar
  17. 17.
    Carswell, H. V., Anderson, N. H., Clark, J. S., et al. (1999) Genetic and gender influences on sensitivity to focal cerebral ischemia in the stroke-prone spontaneously hypertensive rat. Hypertension 33, 681–685.PubMedGoogle Scholar
  18. 18.
    Fujii, K., Weno, B. L., Baumbach, G. L., Heistad, D. D. (1992) Effect of antihypertensive treatment on focal cerebral infarction. Hypertension 19, 713–716.PubMedGoogle Scholar
  19. 19.
    Coyle, P. (1984) Outcomes to middle cerebral artery occlusion in hypertensive and normotensive rats. Hypertension 6(2 Pt 2), I69–74.PubMedGoogle Scholar
  20. 20.
    Bihoreau, M.T., Gauguier, D., Kato, N., et al. (1997) A linkage map of the rat genome derived from three F2 crosses. Genome Res. 7, 434–440.PubMedGoogle Scholar
  21. 21.
    Steen, R. G, Kwitek-Black, A. E., Glenn, C, et al. (1999). A high-density integrated genetic linkage and radiation hybrid map of the laboratory rat. Genome Res. 9, AP1–AP8.PubMedGoogle Scholar
  22. 22.
    Frantz, S. A., Kaiser, M., Gardiner, S., et al. (1998) Successful isolation of a rat chromosome 1 blood pressure QTL in reciprocal congenic strain. Hypertension 32, 639–646.PubMedGoogle Scholar
  23. 23.
    Morel, L., Yu, Y., Blenman, K. R., Caldwell, R. A., Wakeland, E. K. (1996) Production of congenic mouse strains carrying genomic intervals containing SLE-susceptibility genes derived from the SLE-prone NZM2410 strain. Mammalian Genome 7, 335–339.PubMedCrossRefGoogle Scholar
  24. 24.
    Jeffs, B., Negrin, C. D., Graham, D., et al. (2000). Applicability of a speed congenic strategy to dissect blood pressure QTL on rat chromosome 2. Hypertension 35, 179–187.PubMedGoogle Scholar
  25. 25.
    Lander, E. S. and Schork, N. J. (1994) Genetic dissection of complex traits. Science 265, 2037–2048.PubMedCrossRefGoogle Scholar
  26. 26.
    Macrae, I. M. (1992) New models of focal cerebral ischaemia [Review]. Br. J. Clin. Pharmacol. 34, 302–308.Google Scholar
  27. 27.
    Osborne, K. A., Shigeno, T., Balarsky, A. M., et al. (1987) Quantitative assessment of early brain damage in a rat model of focal cerebral ischaemia. J. Neurol. Neurosurg. Psychiatry 50, 402–410.PubMedCrossRefGoogle Scholar
  28. 28.
    Wakeland, E., Morel, L., Achey, K., Yui, M., and Longmate, J. (1997) Speed congenics: a classic technique in the fast lane (relatively speaking). Immunol. Today 18, 472–477.PubMedCrossRefGoogle Scholar
  29. 29.
    Markel, P., Shu, P., Ebeling, C, et al. (1997) Theoretical and empirical issues for marker-assisted breeding of congenic mouse strains. Nat. Genet. 17, 280–284.PubMedCrossRefGoogle Scholar
  30. 30.
    Hurn, P. D. and Macrae, I. M. (2000) Estrogen as a neuroprotectant in stroke. J. Cereb. Blood Flow Metab. 20, 631–652.PubMedCrossRefGoogle Scholar
  31. 31.
    Carswell, H. V., Dominiczak, A. F., Macrae, I. M. (2000a) Estrogen status affects sensitivity to focal cerebral ischemia in stroke-prone spontaneously hypertensive rats. Am. J. Physiol. Heart Circ. Physiol. 278, H290–H294PubMedGoogle Scholar
  32. 32.
    Bederson, J. B., Pitts, L. H., Germano, S. M., Nishimura, M. C, Davis, R. L., Bartkowski, H. M. (1986) Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke 17, 1304–1308.PubMedGoogle Scholar
  33. 33.
    Hatfield, R. H., Mendelow, A. D., Perry, R. H., Alvarez, L. M., Modha, P. (1991) Triphenyltetrazolium chloride (TTC) as a marker for ischaemic changes in rat brain following permanent middle cerebral artery occlusion. Neuropathol. Appl. Neurobiol. 117, 61–67.CrossRefGoogle Scholar
  34. 34.
    Liszczak, T. M., Hedley-Whyte, E. T., Adams, J. F., et al. (1984) Limitations of tetrazolium salts in delineating infarcted brain. Acta. Neuropathol. (Berl) 65, 150–157.CrossRefGoogle Scholar
  35. 35.
    Swanson, R. A., Morton, M. T., Tsao-Wu, G., Savalos, R. A., Davidson, C, Sharp, F. R. (1990) A semiautomated method for measuring brain infarct volume. J. Cereb. Blood Flow Metab. 10, 290–293.PubMedGoogle Scholar
  36. 36.
    Rubattu, S., Volpe, M., Kreutz, R., Ganten, U., Ganten, D., Lindpaintner, K. (1996) Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease. Nat. Genet. 13, 429–434.PubMedCrossRefGoogle Scholar
  37. 37.
    Ikeda, K., Nara, Y., Matumoto, C, et al. (1996) The region responsible for stroke on chromosome 4 in the stroke-prone spontaneously hypertensive rat. Biochem. Biophys. Res. Commun. 229, 658–662.PubMedCrossRefGoogle Scholar
  38. 38.
    Kato, N., Tamada, T., Nabika, T., et al. (2000) Identification of quantitative trait loci for serum cholesterol levels in stroke-prone spontaneously hypertensive rats. Arterioscler. Thromb. Vase. Biol. 20, 223–229.Google Scholar
  39. 39.
    Rubattu, S., Ganten, U., Volpe, M., and Lindpainter, K. (1999) Increased incidence of stroke in congenic rats carrying the SHRSP-derived stroke-related locus, STR-1. Circulation 100,Suppl 1.Google Scholar
  40. 40.
    Garrett, M. R., Dene, H., Walder, R., et al. (1998) Genome scan and congenic strains for blood pressure QTL using Dahl salt-sensitive rats. Genome Res. 8, 711–723.PubMedGoogle Scholar
  41. 41.
    Deng, A. Y., Dene, H., Rapp, J. P. (1997) Congenic strains for the blood pressure quantitative trait locus on rat chromosome 2. Hypertension 30, 199–202.PubMedGoogle Scholar
  42. 42.
    Alemayehu, A., Breen, L., Krenova, D., Printz, M. P. (2002) Reciprocal rat chromosome 2 congenic strains reveal contrasting blood pressure and heart rate QTL. Physiol. Genomics 10, 199–210.PubMedGoogle Scholar
  43. 43.
    Jiang, J., Stec, D. E., Drummond, H., et al. (1997) Transfer of a salt-resistant renin allele raises blood pressure in Dahl salt-sensitive rats. Hypertension 29, 619–627.PubMedGoogle Scholar
  44. 44.
    Aitman, T. J., Glazier, A. M., Wallace, C. A., et al. (1999) Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats. Nat. Genet. 21, 76–83.PubMedCrossRefGoogle Scholar
  45. 45.
    Kirsch, T., Wellner, M., Luft, F. C, Haller, H., Lippoldt, A. (2001) Altered gene expression in cerebral capillaries of stroke-prone spontaneously hypertensive rats. Brain Res. 910, 106–115.PubMedCrossRefGoogle Scholar
  46. 46.
    Brosnan, M. J., Clark, J. S., Jeffs, B., et al. (1999) Genes encoding atrial and brain natriuretic peptides as candidates for sensitivity to brain ischemia in stroke-prone hypertensive rats. Hypertension 33, 290–297.PubMedGoogle Scholar
  47. 47.
    Rubattu, S., Lee-Kirsch, M. A., DePaolis, P., et al. (1999) Altered structure, regulation, and function of the gene encoding the atrial natriuretic peptide in the stroke-prone spontaneously hypertensive rat. Circ. Res. 85, 900–905.PubMedGoogle Scholar
  48. 48.
    De Lange, R. P., Burr, K., Clark, J. S., et al. (2001) Mapping and sequencing rat dishevelled-1: a candidate gene for cerebral ischaemic insult in a rat model of stroke. Neurogenetics 3, 99–106.PubMedCrossRefGoogle Scholar
  49. 49.
    Sharp, F. R., Lu, A., Tang, Y., Millhorn, D. E. (2000) Multiple molecular penumbras after focal cerebral ischemia. J. Cereb. Blood Flow Metab. 20, 1011–32.PubMedCrossRefGoogle Scholar
  50. 50.
    Kimoto, S., Nishida, S., Funasaka, K., Nakano, T., Teramoto, K., and Tomura, T. T. (1995) Regional distribution of superoxide dismutase in the brain and myocardium of the stroke-prone spontaneously hypertensive rat. Clin. Exp. Pharmacol. Physiol. Suppl. 22, S160–S161.PubMedCrossRefGoogle Scholar
  51. 51.
    Ito, H., Torii, M., Suzuki, T. (1993) A comparative study on lipid peroxidation in cerebral cortex of stroke-prone spontaneously hypertensive and normotensive rats. Int. J. Biochem. 25, 1801–1805.PubMedGoogle Scholar
  52. 52.
    Coyle, P. and Heistad, D. D. (1991) Development of collaterals in the cerebral circulation. Blood Vessels 28, 183–189.PubMedGoogle Scholar
  53. 53.
    Carswell, H. V., Anderson, N. H., Morton, J. J., McCulloch, J., Dominiczak, A. F., Macrae, I. M. (2000b) Investigation of estrogen status and increased stroke sensitivity on cerebral blood flow after a focal ischemic insult. J. Cereb. Blood Flow Metab. 20, 931–936.PubMedCrossRefGoogle Scholar
  54. 54.
    Rubattu, S., Giliberti, R., Russo, R., Gigante, B., Ganten, U., Volpe, M. (2000) Analysis of the genetic basis of the endothelium-dependent impaired vasorelaxation in the stroke-prone spontaneously hypertensive rat: a candidate gene approach. J. Hypertens. 18, 161–165.PubMedCrossRefGoogle Scholar
  55. 55.
    Wang, M. M., Klaus, J. A., Joh, H. D., Traystman, R. J., Hurn, P. D. (2002) Postishemic angiogenic factor expression in stroke-prone rats. Exp. Neurol. 173, 283–288.PubMedCrossRefGoogle Scholar
  56. 56.
    Takemori, K., Ito, H., Suzuki, T. (2000) Effects of the AT1 receptor antagonist on adhesion molecule expression in leukocytes and brain microvessels of stroke-prone spontaneously hypertensive rats. Am. J. Hypertens. 13, 1233–1241.PubMedCrossRefGoogle Scholar
  57. 57.
    Yamagata, K., Tagami, M., Ikeda, K., Yamori, Y., Nara, Y. (2000) Altered gene expressions during hypoxia and reoxygenation in cortical neurons isolated from stroke-prone spontaneously hypertensive rats. Neurosci. Lett. 284, 131–134.PubMedCrossRefGoogle Scholar
  58. 58.
    Tagami, M., Ikeda, K., Nara, Y., et al. (1997) Insulin-like growth factor-1 attenuates apoptosis in hippocampal neurons caused by cerebral ischemia and reperfusion in stroke-pronespontaneously hypertensive rats. Lab. Invest. 76, 613–617.PubMedGoogle Scholar
  59. 59.
    Negrin, C. D., McBride, M. W., Carswell, H. V., et al. (2001) Reciprocal consomic strains to evaluate Y chromosome effects. Hypertension 37, 391–397.PubMedGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2005

Authors and Affiliations

  • Hilary V. O. Carswell
    • 1
  • Martin W. McBride
    • 2
  • Delyth Graham
    • 2
  • Anna F. Dominiczak
    • 2
  • I. Mhairi Macrae
    • 1
  1. 1.Division of Clinical Neuroscience, Wellcome Surgical InstituteUniversity of GlasgowGlasgow, ScotlandUK
  2. 2.BHF Glasgow Cardiovascular Research CentreUniversity of GlasgowGlasgow, ScotlandUK

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