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The Genomics of Cardiovascular Disorders

Therapeutic Implications

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Abstract

Cardiovascular disease (CVD) is a complicated series of disorders that result from the interaction between genetic predisposing mechanisms and environmental factors. Over the last few years substantial progress has been made in defining the molecular basis of several genetically transmitted non-atherosclerotic CVD such as hypertrophic and dilated cardiomyopathies, long-QT syndrome and essential hypertension. This review represents a summary of the current knowledge about the major gene polymorphisms found to be associated with these CVDs. Moreover, we will discuss how the discovery of disease-associated genes will greatly enhance the ability to formulate advanced diagnoses, to define prophylactic therapeutic strategies to prevent or reduce the progression of the disease and, finally, to proceed to the development of new drugs tailored for the specific cellular or molecular functions altered as consequence of the predisposing genes.

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References

  1. Schork JK. Genetically complex cardiovascular traits origins, problems, and potential solutions. Hypertension 1997; 29(Pt 2): 145–9

    Article  PubMed  CAS  Google Scholar 

  2. Collins FS, Patrinos A, Jordan E, et al. New goals for the U.S. human genome project: 1998–2003. Science 1997; 282: 682–9

    Article  Google Scholar 

  3. Collins FS. Positional cloning moves from perditional to traditional. Nat Genet 1995; 9: 347–50

    Article  PubMed  CAS  Google Scholar 

  4. Duboule D, Wilkins AS. The evolution of ‘bricolage’. Trends Genet 1998; 14: 54–9

    Article  PubMed  CAS  Google Scholar 

  5. Maron BJ, Bonow RO, Leon MB, et al. Hypertrophic cardio-myopathy: interrelations of clinical manifestations, pathophysiology, and therapy. N Engl J Med 1987; 316: 780–9, 844-52

    Article  PubMed  CAS  Google Scholar 

  6. Wigle ED, Rakowski H, Kimball, et al. Hypertrophic cardiomyopathy: clinical spectrum and treatment. Circulation 1995; 92: 1680–92

    Article  PubMed  CAS  Google Scholar 

  7. Bonne G, Carrier L, Richard P, et al. Familial hypertrophic cardiomyopathy from mutations to functional defects. Circ Res 1998; 83: 580–93

    Article  PubMed  CAS  Google Scholar 

  8. Anan R, Greve G, Thierfelder L, et al. Prognostic implications of novel β-cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy. J Clin Invest 1994; 93: 280–5

    Article  PubMed  CAS  Google Scholar 

  9. Poetter K, Jiang H, Hassanzadeh S, et al. Mutation in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. Nat Genet 1996; 13: 63–9

    Article  PubMed  CAS  Google Scholar 

  10. Flavigny J, Richard P, Isnard R, et al. Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy. J Mol Med 1998; 76: 208–14

    Article  PubMed  CAS  Google Scholar 

  11. Sweeney HL, Huisheng SF, Yang Z, et al. Functional analyses of troponin T mutations that cause hypertrophic cardiomyopathy: insights into disease pathogenesis and troponin function. Proc Natl Acad Sci U S A 1998; 95: 14406–10

    Article  PubMed  CAS  Google Scholar 

  12. Kimura A, Harada H, Park JE et al. Mutation in the cardiac troponin I associated with hypertrophic cardiomyopathy. Nat Genet 1997; 16: 379–82

    Article  PubMed  CAS  Google Scholar 

  13. Yamauchi-Takihara K, Nakajima-Taniguchi C, Matsui H, et al. Clinical implications of hypertrophic cardiomiopathy associated with mutations in the α-tropmyosin gene. Heart 1996; 76: 63–5

    Article  PubMed  CAS  Google Scholar 

  14. Carrier L, Bonne G, Bahrend E, et al. Organization and sequence of human cardiac myosin binding protein C gene (MYBPC3) and identification of mutations predicted to produce truncated proteins in familial hypertrophic cardiomyopathy. Circ Res 1997; 80: 427–34

    PubMed  CAS  Google Scholar 

  15. Watkins H, Corner D, Thierfelder L, et al. Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. Nat Genet 1995; 11: 434–7

    Article  PubMed  CAS  Google Scholar 

  16. Nimura H, Bachinski LL, Sangwatanaroj S. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med 1998; 338: 1248–57

    Article  Google Scholar 

  17. MacRae CA, Ghaisas N, Kass S, et al. Familial hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome maps to a locus on chromosome 7q3. J Clin Invest 1995; 9: 1216–20

    Article  Google Scholar 

  18. Watkins H, Roenzweig A, Hwang DS, et al. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med 1992; 326(17): 1108–14

    Article  PubMed  CAS  Google Scholar 

  19. Tesson F, Richard P, Charron P, et al. Genotype-phenotype analysis in four families with mutations in beta-myosin heavy chain gene responsible for familial hypertrophic cardiomyopathy. Hum Mutat 1998; 12(6): 385–92

    Article  PubMed  CAS  Google Scholar 

  20. Hwang T-H, Lee W-H, Kimura A, et al. Early expression of a malignant phenotype of familial hypertrophic cardiomyopathy associated with a Gly716Arg myosin heavy chain mutation in a korean family. Am J Cardiol 1998; 82: 1509–13

    Article  PubMed  CAS  Google Scholar 

  21. Sweeney HL, Straceski Aj, Leinwand LA, et al. Heterologous expression of a cardiomyopathic myosin that is a defective in its actin interaction. J Biol Chem 1994; 269: 1603–5

    PubMed  CAS  Google Scholar 

  22. Geisterfer-Lowrance AAT, Christe M, Conner DA, et al. A mouse model of a familial hypertrophic cardiomyopathy. Science 1996; 2: 731–4

    Article  Google Scholar 

  23. Wikstrom KL, Factor SM, Leinwand LA. Mice expressing mutant myosin heavy chains are a model for familial hypertrophic cardiomyopathy. Mol Med 1996; 2: 556–67

    Google Scholar 

  24. Cuda G, Fananapazir L, Epstein ND, et al. The in vitro motility activity of beta-cardiac myosin depends on the nature of the beta-myosin heavy chain gene mutation in hypertrophic cardiomyopathy. J Muscle Res Cell Motil 1997; 18: 275–83

    Article  PubMed  CAS  Google Scholar 

  25. Tierfelder L, Watkins H, MacRae C, et al. α-Tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell 1994; 77: 701–12

    Article  Google Scholar 

  26. Watkins H, McKenna WJ, Thierfelder L, et al. Mutations in the genes for cardiac troponin T and α-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med 1995; 332: 1058–64

    Article  PubMed  CAS  Google Scholar 

  27. Bonne G, Carrier L, Bercovici J, et al. Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy. Nat Genet 1995; 11: 438–40

    Article  PubMed  CAS  Google Scholar 

  28. Yu B, French JA, Carrier L, et al. Molecular pathology of familial hypertrophic cardiomyopathy caused by mutations in the cardiac myosin binding protein C gene. J Med Genet 1998; 35(3): 205–10

    Article  PubMed  CAS  Google Scholar 

  29. Charron P, Dubourg O, Desnos M, et al. Clinical feature and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene. Circulation 1998; 97: 2230–6

    Article  PubMed  CAS  Google Scholar 

  30. Mogensen J, Klausen IC, Pedersen AK, et al. α-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy. J Clin Invest 1999; 103: 39–43

    Article  Google Scholar 

  31. Osterop A, Kofflard M, Sandkuijl LA, et al. ATl receptor A/C 1166 polymorphism contributes to cardiac hypertrophy in subjects with hypertrophic cardiomyopathy. Hypertension 1998; 32: 825–30

    Article  PubMed  CAS  Google Scholar 

  32. Meastroni L, Rocco C, Vatta M, et al. Advances in molecular genetics of dilated cardiomyopathy. Cardiol Clin 1998; 16: 611–21

    Article  Google Scholar 

  33. Kass S, MacRae C, Graber HL, et al. A gene defect that causes conduction system disease and dilated cardiomyopathy maps to chromosome 1p1-1q1. Nat Genet 1994; 7: 546–51

    Article  PubMed  CAS  Google Scholar 

  34. Durand JB, Bachinski LL, Bieling LC, et al. Localization of a gene responsible for familial dilated cardiomyopathy to chromosome 1q32. Circulation 1995; 92: 3387–9

    Article  PubMed  CAS  Google Scholar 

  35. Olson TM, Keating MT. Mapping a cardiomyopathy locus to chromosome 3p22-p25. J Clin Invest 1996; 97: 528–32

    Article  PubMed  CAS  Google Scholar 

  36. Krajinovich M, Pinamonti B, Sinagra G, et al. Linkage of familial dilated cardiomyopathy to chromosome 9. Am J Hum Genet 1995; 57: 846–52

    Google Scholar 

  37. Bowles KR, Gajarsky R, Porter P, et al. Gene mapping of familial autosomal dominant dilated cardiomyopathy to chromosome 10q21-23. J Clin Invest 1996; 98: 1355–60

    Article  PubMed  CAS  Google Scholar 

  38. Wang J, Wihelmsson H, Graff C, et al. Dilated cardiomyopathy and atrioventricular conduction blocks induced by heartspecific inactivation of mitochondrial DNA gene expression. Nat Genet 1998; 21: 133–7

    Article  CAS  Google Scholar 

  39. Towbin JA, Hejtmancik JF, Brink P, et al. X-linked dilated cardiomyopathy: molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus. Circulation 1993; 87: 1854–65

    Article  PubMed  CAS  Google Scholar 

  40. Ortiz-Lopez R, Li H, Su J, et al. Evidence for a dystrophin missense mutation as a cause of X-linked dilated cardiomyopathy. Circulation 1997; 95: 2434–40

    Article  PubMed  CAS  Google Scholar 

  41. Bione S, D’Adamo P, Maestrin E, et al. A novel X-linked gene, G4.5, is responsible forBarth syndrome. Nat Genet 1996; 12: 385–9

    Article  PubMed  CAS  Google Scholar 

  42. Badorff C, Lee GH, Lamphear BJ, et al. Enteroviral protease 2A cleaves dystrophin: evidence of cytoskeletal disruption in an acquired cardiomyopathy. Nat Med 1999; 5: 321–6

    Google Scholar 

  43. Priori SG, Barhanin J, Hauer RN, et al. Genetic and molecular basis of cardiac arrhythmias impact on clinical management: parts I and II. Circulation 1999; 99: 518–28

    Article  PubMed  CAS  Google Scholar 

  44. Olson TM, Michels W, Thibodeau SN, et al. Actin mutations in dilated cardiomyopathy a heritable form of heart failure. Science 1998; 280: 750–2

    Article  PubMed  CAS  Google Scholar 

  45. Ichihara S, Yamada Y, Yokota M. Association of a G994T missense mutation in the plasma platelet-activating factor acetylhydrolase gene with genetic susceptibility to nonfamilial dilated cardiomyopathy in Japanese. Circulation 1998; 98: 1881–5

    Article  PubMed  CAS  Google Scholar 

  46. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293–302

    Article  Google Scholar 

  47. Raynolds MC, Bristow MR, Bush EW, et al. Angiotensin-converting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy. Lancet 1993; 342: 1073–5

    Article  PubMed  CAS  Google Scholar 

  48. Candy GP, Skudicky D, Mueller K, et al. Association of left ventricular systolic performance and cavity size with angio-tensin-converting enzyme genotype in idiopathic dilated cardiomyopathy. Am J Cardiol 1999; 83: 740–4

    Article  PubMed  CAS  Google Scholar 

  49. Vancura V, Hubaceck J, Malek I, et al. Does angiotensin-converting enzyme polymorphism influence the clinical manifestation and progression of heart failure in patients with dilated cardiomyopathy? Am J Cardiol 1999; 83: 461–2

    Article  PubMed  CAS  Google Scholar 

  50. Loh E, Rebbeck R, Mahoney PD, et al. Common variant in AMPDI gene predicts improved clinical outcome in patients with heart failure. Circulation 1999; 99: 1422–5

    Article  PubMed  CAS  Google Scholar 

  51. Romano C, Gemme C, Pongiglione R. Aritmie cardiache rare dell’età pedriatica. Clin Pediatr 1963; 45: 658–83

    Google Scholar 

  52. Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q–T interval and sudden death. Am Heart J 1957; 54: 59–68

    Article  PubMed  CAS  Google Scholar 

  53. Splawki I, Tristani-Firouzi M, Lehmann MH, et al. Mutation in the hminK gene cause long-QT syndrome and suppress Iκs function. Nat Genet 1997; 17: 338–40

    Article  Google Scholar 

  54. Sanguinetti MC, Curran ME, Spector PS, et al. Spectrum of the Herg K+-channel dysfunction in an inherited cardiac arrhythmia. Proc Natl Acad Sci U S A 1996; 93: 2208–12

    Article  PubMed  CAS  Google Scholar 

  55. Bennet PB, Yazawa K, Makita N, et al. Molecular mechanism for an inherited cardiac arrhythmia. Nature 1995; 376: 683–5

    Article  Google Scholar 

  56. Waagstein F, Bristow MR, Swedberg K, et al. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 1993; 342: 1441–6

    Article  PubMed  CAS  Google Scholar 

  57. CIBIS Investigators and Committees. A randomized trial of b-blockade in heart failure: the cardiac insufficiency bisoprolol study (CIBIS). Circulation 1994; 90: 1765–73

    Article  Google Scholar 

  58. Packer M, Bristow MR, Cohn JN, et al. The effect of cardedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996; 334: 1348–55

    Article  Google Scholar 

  59. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336: 525–33

    Article  Google Scholar 

  60. Nuss B, Marbàn E, Johns DC. Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes. J Clin Invest 1999; 103: 889–96

    Article  PubMed  CAS  Google Scholar 

  61. Dumaine R, Wang Q, Keating MT, et al. Multiple mechanisms of Na+channel-linked long-QT syndrome. Circ Res 1996; 78: 916–24

    Article  PubMed  CAS  Google Scholar 

  62. Xiao YF, Wright SN, Wang GK, et al. Fatty acids suppress voltage-gated Na+currents in HEK293t cells transfected with α-subunit of the human cardiac Na+channel. Proc Natl Acad Sci U S A 1998; 95: 2680–5

    Article  PubMed  CAS  Google Scholar 

  63. Priori SG, Napolitano C, Schwartz PG, et al. KvLQT1 mutation in drug induced torsade de pointes [abstract]. Eur Heart J 1997; 18: 324

    Google Scholar 

  64. Priori SG, Schwartz P, Napolitano C, et al. A recessive variant of the Romano-Ward Long-QT Syndrome? Circulation 1998; 97: 2420–5

    Article  PubMed  CAS  Google Scholar 

  65. Soubrier F, Lathrop GM. The genetic basis of hypertension. Curr Opin Nephrol Hypertens 1995; 4: 177–81

    Article  PubMed  CAS  Google Scholar 

  66. Cusi D, Bianchi G. Genetic and molecular aspects of primary hypertension. In: Birkenhager JL, Reid JL,Robertson JIS, editors. Clinical hypertension. Amsterdam: Elsevier, 1992; 15: 63–94

    Google Scholar 

  67. Hamet P, Pausova Z, Adarichev V, et al. Hypertension: genes and environment. J Hypertension 1998; 16: 397–418

    Article  CAS  Google Scholar 

  68. Ferrari P, Bianchi G. Phannacogenomics in arterial hypertension. In: Dominiczack AF, Connel JMC, Soubrier F, editors. Handbook molecular genetics of hypertension. Oxford: BIOS Scientific Publications Ltd, 1999: 1–13

    Google Scholar 

  69. Guyton AC, Hall JE, Coleman TG, et al. The dominant role of the kidneys in long-term arterial pressure regulation in normal and hypertensive states. In: Laragh JH, Brenner BM, editors. Hypertension: pathophysiology, diagnosis and management. New York (NY): Raven Press Ltd, 1995: 1311–26

    Google Scholar 

  70. Lund-Johansen, Omvik P. Hemodynamic patterns of untreated hypertensive disease. In: Laragh JH, Brenner BM, editors. Hypertension: pathophysiology, diagnosis and management. 2nd ed. New York (NY): Raven Press Ltd, 1995: 323–42

    Google Scholar 

  71. Dominiczack AF, Clark JS, Jeffs V, et al. Genetics of experimental hypertension. J Hypertension 1998; 16: 1859–69

    Article  Google Scholar 

  72. Jeunemaitre X, Soubrier F, Kotelevtsen Y, et al. Molecular basis of human hypertension: role of angiotensinogen. Cell 1992; 71: 169–80

    Article  PubMed  CAS  Google Scholar 

  73. Rigat B, Hubert C, Corvol P, et al. PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dypeptidyl carboxipeptidase 1). Nucleic Acids Res 1992; 20: 1433

    Article  PubMed  CAS  Google Scholar 

  74. Bianchi G, Tripodi G, Casari G. et al. Two point mutations within the adducin genes are involved in blood pressure variation. Proc Natl Acad Sci U S A 1994; 91: 3999–4003

    Article  PubMed  CAS  Google Scholar 

  75. Lindpainter K, Hilbert P, Ganten D, et al. Molecular genetics of the SA gene: cosegregation with hypertension and mapping to rat chromosome 1. Hypertension 1993; 11: 19–23

    Article  Google Scholar 

  76. Svetkey LP, Chen YT, Mckeown SP, et al. Preliminary evidence of a linkage of salt sensitivity in black Americans at the β2-adrenergic receptor locus. Hypertension 1997; 29: 918–22

    Article  PubMed  CAS  Google Scholar 

  77. Siffert W, Rosskopf D, Siffert G et al. Association of a human G-protein beta 3 subunit variant with hypertension. Nat Genet 1998; 18: 8–10

    Article  Google Scholar 

  78. Su YR, Rutkowski MP, Klanke CA, et al. A novel variant of the β-subunit of the amiloride-sensitive sodium channel in African Americans. J Am Soc Nephrol 1996; 7: 2543–9

    PubMed  CAS  Google Scholar 

  79. Casari G, Barlassina C, Cusi D, et al. Association of the α-adducin locus with essential hypertension. Hypertension 1995; 25: 320–6

    Article  PubMed  CAS  Google Scholar 

  80. Cusi D, Barlassina C, Azzani T, et al. Polymorphism of α-adducin and salt sensitivity in patients with essential hypertension. Lancet 1997; 349: 1353–7

    Article  PubMed  CAS  Google Scholar 

  81. Iwai N, Tamaki S, Nakamura Y, et al. Polymorphism of α-adducin and hypertension. Lancet 1997; 350(9074): 369

    Article  PubMed  CAS  Google Scholar 

  82. Schork NJ, Kashkoush SL, Xu X. Hypertension as a complex trait amenable to genetic analysis: basic strategies and integrative approaches. In: Dominiczak AF, Connell JMC, Soubrier F, editors. Molecular genetics of hypertension. Oxford: BIOS Scientific Publications Ltd, 1999: 1–29

    Google Scholar 

  83. Cambien F, Poirier O, Lecerf L, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992; 359: 641–4

    Article  PubMed  CAS  Google Scholar 

  84. Schunkert H, Hense HW, Holmer SR, et al. Association between a deletion polymorphism of the angiotensin-convertingenzyme gene and left ventricular hypertrophy. N Engl J Med 1994; 330: 1634–8

    Article  PubMed  CAS  Google Scholar 

  85. Jeunemaitre X, Lifton RP, Hunt SC, et al. Absence of linkage between the angiotensin converting enzyme locus and human essential hypertension. Nat Genet 1992; 1: 72–5

    Article  PubMed  CAS  Google Scholar 

  86. Collins R, Peto R. Anti-hypertensive therapy: effect in stroke and coronary heart disease. In: Swales JD, editors. Textbook of hypertension. Oxford: Blackwell Scientific, 1994: 1156–64

    Google Scholar 

  87. Swales JD. Pharmacological treatment of hypertension. Lancet 1994; 344: 380–5

    Article  PubMed  CAS  Google Scholar 

  88. Camussi A, Bianchi G. Genetics of essential hypertension from the unimodal-bimodal controversy to molecular technology. Hypertension 1988; 12: 620–8

    Article  PubMed  CAS  Google Scholar 

  89. Veseij ES, Penno MB. Assessment of methods to identify sources of interindividual pharmacokinetic variations. Clin Pharmacol 1983; 8: 378–409

    Article  Google Scholar 

  90. Saunders E, Weir MR, Kong BW. A comparison of the efficacy and safety of a β-blocker, a calcium channel blocker, and a converting enzyme inhibitor in hypertensive blacks. Arch Intern Med 1990;150: 1707–13

    Article  PubMed  CAS  Google Scholar 

  91. Ferrari P. Pharmacogenomics: a new approach to individual therapy of hypertension?. Curr Opin Nephrol Hypertens 1998; 7: 217–22

    Article  PubMed  CAS  Google Scholar 

  92. Pratt ER, Dzau VJ. Genomics and hypertension: concepts, potential and opportunities. Hypertension 1999; 33: 238–47

    Article  PubMed  CAS  Google Scholar 

  93. Dudley C, Keaveney B, Casadei B, et al. Prediction of patient responses to antihypertensive drugs using genetic polymorphism: investigation of renin-angiotensin system genes. J Hypertens 1996; 14: 259–62

    Article  PubMed  CAS  Google Scholar 

  94. Hingorani AD, Jia H, Steven PA. Renin-angiotensin system gene polymorphisms influence blood pressure and the response to angiotensin converting enzyme inhibition. J Hypertens 1995; 13: 1602–9

    PubMed  CAS  Google Scholar 

  95. O’Toole L, Steward M, Padfield P, et al. Effect of the insertion/deletion polymorphism of the angiotensin-converting enzyme gene on response to angiotensin-converting enzyme inhibitors in patients with heart failure. J Cardiovasc Pharmacol 1998; 32: 988–94

    Article  PubMed  Google Scholar 

  96. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: result of the Survival and Left Ventricular Enlargement Trial. N Engl J Med 1992; 327: 669–77

    Article  PubMed  CAS  Google Scholar 

  97. Hunt SC, Geleijnse JM, Wu LL, et al. Enhanced blood pressure response to mild sodium reduction in subjects with the 235T variant of the angiotensinogen gene. Am J Hypertens 1999; 12: 460–6

    Article  PubMed  CAS  Google Scholar 

  98. Vincent M, Samani NJ, Gauguier D, et al. A pharmacogenetic approach to blood pressure in Lyon hypertensive rats: a chromosome 2 locus influences the response to a calcium antagonist. J Clin Invest 1997; 100: 2000–6

    Article  PubMed  CAS  Google Scholar 

  99. Jia H, Hingorani AD, Sharma P, et al. Association of the Gsα gene with essential hypertension and response to β-blockade. Hypertension 1999; 34: 8–14

    Article  PubMed  CAS  Google Scholar 

  100. Bianchi G, Baer PG, Fox U, et al. Changes in renin, water balance and sodium balance during development of high blood pressure in genetically hypertensive rats. Circ Res 1975; 36 (6) Suppl. 1: 153–61

    Article  Google Scholar 

  101. Bianchi G, Fox U, Di Francesco GF, et al. The hypertensive role of the kidney in spontaneously hypertensive rats. Clin Sci Mol Med 1973; 45 Suppl. 1: 135–9

    Google Scholar 

  102. Bianchi G, Fox U, Di Francesco GF, et al. Blood pressure changes produced by kidney cross-transplantation between spontaneously hypertensive rats and normotensive rats. Clin Sci Mol Med 1974; 47: 435–48

    PubMed  CAS  Google Scholar 

  103. Ferrari P, Bianchi G. Lessons from experimental genetic hypertension. In: Laragh JH, Brenner BM, editors. Hypertension pathophysiology, diagnosis and management. New York (NY): Raven Press Ltd, 1995: 1261–80

    Google Scholar 

  104. Ferrandi M, Tripodi G, Salardi S, et al. Renal Na-KATPase in genetic hypertension. Hypertension 1996; 28: 1018–25

    Article  PubMed  CAS  Google Scholar 

  105. Hughes CA, Bennet V Adducin a physical model with implications for function in assembly of spectrin-actin complexes. J Biol Chem 1995; 270: 18990–6

    Article  PubMed  CAS  Google Scholar 

  106. Gardner K, Bennet V A new erythrocyte membrane-associated protein with calmodulin binding activity. J Biol Chem 1986; 261(3): 1339–48

    PubMed  CAS  Google Scholar 

  107. Matsuoka Y, Hughes CA, Bennet V Definition of the calmodulin-binding domain and sites of phosphorylation by protein kinase A and C. J Biol Chem 1996; 271: 25157–66

    Article  PubMed  CAS  Google Scholar 

  108. Aderem A. The MARCKS brothers: a family of protein kinase C substrate. Cell 1992; 71: 713–16

    Article  PubMed  CAS  Google Scholar 

  109. Tripodi G, Valtorta F, Torielli L, et al. Hypertension associated point mutations in the α and β subunits affect actin cytoskeleton and ion transport. J Clin Invest 1997; 2815-22

  110. Ferrandi M, Salardi S, Tripodi G, et al. Interaction between adducin and Na, K-ATPase. differential effect on hypertension related human and rat adducin polymorphisms. Am J Physiol 1999; 277: H1338–49

    PubMed  CAS  Google Scholar 

  111. Ferrandi M, Minotti E, Salardi S, et al. Ouabain-like factor in Milan hypertensive rats. Am J Physiol 1992; 263: F739–48

    PubMed  CAS  Google Scholar 

  112. Ferrandi M, Manunta P, Balzan S, et al. Ouabain-like factor quantification in mammalian tissues and plasma: comparison of two independent assays. Hypertension 1997; 30: 886–96

    Article  PubMed  CAS  Google Scholar 

  113. Castellano M, Barlassina C, Muiesan ML, et al. Alpha-adducin gene polymorphism and cardiovascular phenotypes in a general population. J Hypertension 1997, 15: 1707–10

    Article  CAS  Google Scholar 

  114. Manunta P, Cusi D, Barlassina C, et al. α-Adducin polymorphisms and renal sodium handling in essential hypertensive patients. Kidney Int 1998; 53: 1471–8

    Article  PubMed  CAS  Google Scholar 

  115. Ishikawa K, Katsuya T, Sato N, et al. No association between α-adducin 460 polymorphism and essential hypertension in a Japanese population. Am J Hypertension 1998; 11: 502–6

    Article  CAS  Google Scholar 

  116. Kato N, Sugiyama T, Nabika T, et al. Lack of association between the alpha-adducin locus and essential hypertension in the Japanese population. Hypertension 1998, 31: 730–3

    Article  PubMed  CAS  Google Scholar 

  117. Glorioso N, Manunta P, Filigheddu F, et al. The role of α-adducin polymorphism in blood pressure and sodium handling regulation may not be excluded by a negative association study. Hypertension 1999; 34: 649–54

    Article  PubMed  CAS  Google Scholar 

  118. Manunta P, Stella P, Rivera R, et al. Left ventricular mass, stroke volume and ouabain-like factor. Hypertension 1999; 34: 450–6

    Article  PubMed  CAS  Google Scholar 

  119. Ferrari P, Torielli L, Ferrandi M, et al. PST 2238: a new antihypertensive compound that antagonizes the long-term pressor effect of ouabain. J Pharmacol Exp Ther 1998; 285: 83–94

    PubMed  CAS  Google Scholar 

  120. Pollack LR, Tate EH, Cook JS. Na+-K+-ATPase in HeLa cells after prolonged growth in low K+ or ouabain. J Cell Physiol 1988; 106: 85–97

    Article  Google Scholar 

  121. Rayson BM, Gupta RK. Steroids, intracellular sodium levels, and Na-K ATPase regulation. J Biol Chem 1985; 260: 12740–3

    PubMed  CAS  Google Scholar 

  122. Ferrari P, Torielli L, Ferrandi M, et al. PST 2238: a new antihypertensive compound that modulates Na-KATPase and antagonizes the pressor effect of OLE Cardiovasc Drug Rev 1999; 17: 39–57

    CAS  Google Scholar 

  123. Ferrari P, Ferrandi M, Tripodi G, et al. PST 2238: a new anti-hypertensive compound that modulates Na, K-ATPase in genetic hypertension. J Pharmacol Exp Ther 1999; 288(3): 1074–83

    PubMed  CAS  Google Scholar 

  124. Tripodi G, Szpirer C, Reina C, et al. Polymorphism of α-adducin gene in genetic hypertension and mapping of the gene to rat chromosome 1q55. Biochem Biophys Res Comm 1997; 237: 685–9

    Article  PubMed  CAS  Google Scholar 

  125. Nguyen AT, Hayward-Lester A, Sabatini S, et al. Renal Na-K ATPase in SHR: studies of activity and gene expression. Clin Exp Hypertens 1998; 20(5&6): 641–6

    Article  PubMed  CAS  Google Scholar 

  126. Doris PA. Ouabain in plasma from spontaneously hypertensive rats. Am J Physiol 1994; 266: H360–4

    PubMed  CAS  Google Scholar 

  127. Rayson BM. Rates of synthesis and degradation of Na+-K+-ATPase during chronic ouabain treatment. Am J Physiol 1989; 256(1 Pt 1): C75–80

    PubMed  CAS  Google Scholar 

  128. Tang M-J, McDonough AA. Low K+ increases Na+-K+-ATPase α-and β-subunit mRNA and protein abundance in cultured renal proximal tubule cells. Am J Physiol 1992; 263: C436–42

    PubMed  CAS  Google Scholar 

  129. Wang X, Feuerstein GZ. The use of mRNA differential display for discovery of novel therapeutic targets in cardiovascular disease. Cardiovasc Res 1997, 35: 414–21

    Article  PubMed  CAS  Google Scholar 

  130. Debouck C, Goodfellow PN. DNA microarrays in drug discovery and development. Nat Genet 1999; 21: 48–50

    Article  PubMed  CAS  Google Scholar 

  131. Sander ES. Array of hope. Nat Genet 1999; 21: 3–4

    Article  Google Scholar 

  132. Duggan DJ, Bittner M, Chen Y, et al. Expression profiling using cDNA microarrays. Nat Genet 1999; 21: 10–14

    Article  PubMed  CAS  Google Scholar 

  133. Muller S, Neumann T, Lottspeich F. Proteomics: a new way for drug discovery. Arzneimittelforschung 1998; 48: 93–5

    Google Scholar 

  134. Barlassina C, Schork NJ, Manunta P, et al. Synergistic effect of α-adducin and ACE genes in causing blood pressure changes with body sodium and volume expansion. Kidney Int. In press

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Authors and Affiliations

  1. Prassis Sigma-Tau Research Institute, Settimo Milanese, Milan, Italy

    Patrizia Ferrari

  2. Division of Nephrology, Dialysis and Hypertension, San Raffaele Hospital, Milan University, Via Olgettina 60, 20132, Milan, Italy

    Giuseppe Bianchi (Chair of Nephrology)

Authors
  1. Patrizia Ferrari
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  2. Giuseppe Bianchi
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Correspondence to Giuseppe Bianchi.

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Ferrari, P., Bianchi, G. The Genomics of Cardiovascular Disorders. Drugs 59, 1025–1042 (2000). https://doi.org/10.2165/00003495-200059050-00001

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  • DOI: https://doi.org/10.2165/00003495-200059050-00001

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