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Control of cardiomyocyte gene expression as drug target

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Abstract

Pressure overload of the heart is associated with a perturbed gene expression of the cardiomyocyte leading to an impaired pump function. The ensuing neuro-endocrine activation results in disordered influences of angiotensin II and catecholamines on gene expression. To assess whether angiotensin II type 1 receptor inhibition can also counteract a raised sympathetic nervous system activity, spontaneously hypertensive rats fed a hypercaloric diet were treated with eprosartan (daily 90 mg/kg body wt) and cardiovascular parameters were monitored with implanted radiotelemetry pressure transducers. Both, blood pressure and heart rate were increased (p < 0.05) by the hypercaloric diet. Although eprosartan reduced (p < 0.05) the raised systolic and diastolic blood pressure, the diet-induced rise in heart rate was blunted only partially. In addition to drugs interfering with the enhanced catecholamine influence, compounds should be considered that selectively affect cardiomyocyte gene expression via 'metabolic' signals.

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References

  1. Lenfant C, Roccella EJ: A call to action for more aggressive treatment of hypertension. J Hypertens 17(suppl): S3–S7, 1999

    Google Scholar 

  2. Nakao K, Minobe W, Roden R, Bristow MR, Leinwand LA: Myosin heavy chain gene expression in human heart failure. J Clin Invest 100: 2362–2370, 1997

    Google Scholar 

  3. Miyata S, Minobe W, Bristow MR, Leinwand LA: Myosin heavy chain isoform expression in the failing and non-failing human heart. Circ Res 86: 386–390, 2000

    Google Scholar 

  4. Lowes BD, Minobe W, Abraham WT, Rizeq MN, Bohlmeyer TJ, Quaife RA, Roden RL, Dutcher DL, Robertson AD, Voelkel NF, Badesch DB, Groves BM, Gilbert EM, Bristow MR: Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium. J Clin Invest 100: 2315–2324, 1997

    Google Scholar 

  5. Morkin E, Pennock GD, Raya TE, Bahl JJ, Goldman S: Development of a thyroid hormone analogue for the treatment of congestive heart failure. Thyroid 6: 521–526, 1996

    Google Scholar 

  6. Mahaffey KW, Raya TE, Pennock GD, Morkin E, Goldman S: Left ventricular performance and remodeling in rabbits after myocardial infarction. Effects of a thyroid hormone analogue. Circulation 91: 794–801, 1995

    Google Scholar 

  7. Spooner PH, Morkin E, Goldman S: Thyroid hormone and thyroid hormone analogues in the treatment of heart failure. Coron Artery Dis 10: 395–399, 1999

    Google Scholar 

  8. Rupp H, Berger HJ, Pfeifer A, Werdan K: Effect of positive inotropic agents on myosin isozyme population and mechanical activity of cultured rat heart myocytes. Circ Res 68: 1164–1173, 1991

    Google Scholar 

  9. Muller-Werdan U, Pfeifer A, Hubner G, Seliger C, Reithmann C, Rupp H, Werdan K: Partial inhibition of protein synthesis by Pseudomonas exotoxin A deranges catecholamine sensitivity of cultured rat heart myocytes. J Mol Cell Cardiol 29: 799–811, 1997

    Google Scholar 

  10. Gupta MP, Gupta M, Zak R: An E-box/M-CAT hybrid motif and cognate binding protein(s) regulate the basal muscle-specific and cAMPinducible expression of the rat cardiac alpha-myosin heavy chain gene. J Biol Chem 269: 29677–29687, 1994

    Google Scholar 

  11. Gupta MP, Gupta M, Dizon E, Zak R: Sympathetic control of cardiac myosin heavy chain gene expression. Mol Cell Biochem 157: 117–124, 1996

    Google Scholar 

  12. Rupp H, Wahl R: Influence of thyroid hormones and catecholamines on myosin of swim-exercised rats. J Appl Physiol 68: 973–978, 1990

    Google Scholar 

  13. Ohkubo T, Jacob R, Rupp H: Swimming changes vascular fatty acid composition and prostanoid generation of rats. Am J Physiol 262: R464–R471, 1992

    Google Scholar 

  14. Rupp H, Elimban V, Dhalla NS: Diabetes-like action of intermittent fasting on sarcoplasmic reticulum Ca2+-pump ATPase and myosin isoenzymes can be prevented by sucrose. Biochem Biophys Res Commun 164: 319–325, 1989

    Google Scholar 

  15. Rupp H, Wahl R, Jacob R: Remodelling of the myocyte at a molecular level–relationship between myosin isozyme population and sarcoplasmic reticulum. In: N.S. Dhalla, G.N. Pierce, R.E. Beamish (eds). Heart Function and Metabolism. Martinus Nijhoff Publishing, Boston, 1987, p. 307

    Google Scholar 

  16. Fukase N, Takahashi H, Manaka H, Igarashi M, Yamatani K, Daimon M, Sugiyama K, Tominaga M, Sasaki H: Differences in glucagon-like peptide-1 and GIP responses following sucrose ingestion. Diabetes Res Clin Pract 15: 187–195, 1992

    Google Scholar 

  17. Rupp H, Elimban V, Dhalla NS: Differential influence of fasting and BM13.907 treatment on growth and phenotype of pressure overloaded rat heart. Mol Cell Biochem 188: 209–215, 1998

    Google Scholar 

  18. Jacob R, Brandle M, Dierberger B, Rupp H: Functional consequences of cardiac hypertrophy and dilatation. Basic Res Cardiol 86(suppl 1): 113–130, 1991

    Google Scholar 

  19. Turcani M, Rupp H: Heart failure development in rats with ascending aortic constriction and angiotensin-converting enzyme inhibition. Br J Pharmacol (in press)

  20. Turcani M, Rupp H: Development of pressure overload induced cardiac hypertrophy is unaffected by long-term treatment with losartan. Mol Cell Biochem 188: 225–233, 1998

    Google Scholar 

  21. Brandt JM, Djouadi F, Kelly DP: Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha. J Biol Chem 273: 23786–23792, 1998

    Google Scholar 

  22. Turcani M, Rupp H: Etomoxir improves left ventricular performance of pressure-overloaded rat heart. Circulation 96: 3681–3686, 1997

    Google Scholar 

  23. Turcani M, Rupp H: Modification of left ventricular hypertrophy by chronic etomixir treatment. Br J Pharmacol 126: 501–507, 1999

    Google Scholar 

  24. Rupp H, Elimban V, Dhalla NS: Sucrose feeding prevents changes in myosin isoenzymes and sarcoplasmic reticulum Ca2+-pump ATPase in pressure-loaded rat heart. Biochem Biophys Res Commun 156: 917–923, 1988

    Google Scholar 

  25. Turcani M, Rupp H: Bradykinin (B2) independent effect of captopril on the development of pressure overload cardiac hypertrophy. Mol Cell Biochem 212: 219–225, 2000

    Google Scholar 

  26. Lithell HO: Insulin resistance and diabetes in the context of treatment of hypertension. Blood Press 3(suppl): 28–31, 1998

    Google Scholar 

  27. Anderson B, Khaper N, Dhalla AK, Singal PK: Anti-free radical mechanisms in captopril protection against reperfusion injury in isolated rat hearts. Can J Cardiol 12: 1099–1104, 1996

    Google Scholar 

  28. Obermaier-Kusser B, Muhlbacher C, Mushack J, Seffer E, Ermel B, Machicao F, Schmidt F, Haring HU: Further evidence for a two-step model of glucose-transport regulation. Inositol phosphate-oligosaccharides regulate glucose-carrier activity. Biochem J 261: 699–705, 1989

    Google Scholar 

  29. Pagani ED, Solaro RJ: Coordination of cardiac myofibrillar and sarcotubular activities in rats exercised by swimming. Am J Physiol 247: H909–H915, 1984

    Google Scholar 

  30. Rupp H, Wahl R, Hansen M: Influence of diet and carnitine palmitoyltransferase I inhibition on myosin and sarcoplasmic reticulum. J Appl Physiol 72: 352–360, 1992

    Google Scholar 

  31. Zarain-Herzberg A, Rupp H, Elimban V, Dhalla NS: Modification of sarcoplasmic reticulum gene expression in pressure overload cardiac hypertrophy by etomoxir. FASEB J 10: 1303–1309, 1996

    Google Scholar 

  32. Zarain-Herzberg A, Rupp H: Transcriptional modulators targeted at fuel metabolism of hypertrophied heart. Am J Cardiol 83: 31H–37H, 1999

    Google Scholar 

  33. Weber KT, Brilla CG: Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation 83: 1849–1865, 1991

    Google Scholar 

  34. Muller FU, Boknik P, Knapp J, Neumann J, Vahlensieck U, Oetjen E, Scheld HH, Schmitz W: Identification and expression of a novel isoform of cAMP response element modulator in the human heart. FASEB J 12: 1191–1199, 1998

    Google Scholar 

  35. Brilla CG, Zhou G, Matsubara L, Weber KT: Collagen metabolism in cultured adult rat cardiac fibroblasts: Response to angiotensin II and aldosterone. J Mol Cell Cardiol 26: 809–820, 1994

    Google Scholar 

  36. Yamazaki T, Shiojima I, Komuro I, Nagai R, Yazaki Y: Involvement of the renin-angiotensin system in the development of left ventricular hypertrophy and dysfunction. J Hypertens 12(suppl): S23–S27, 1994

    Google Scholar 

  37. Jacob R, Kissling G, Rupp H, Vogt M: Functional significance of contractile proteins in cardiac hypertrophy and failure. J Cardiovasc Pharmacol 10(suppl 6): S2–S12, 1987

    Google Scholar 

  38. Asano K, Dutcher DL, Port JD, Minobe WA, Tremmel KD, Roden RL, Bohlmeyer TJ, Bush EW, Jenkin MJ, Abraham WT, Raynolds MV, Zisman LS, Perryman MB, Bristow MR: Selective downregulation of the angiotensin II AT1-receptor subtype in failing human ventricular myocardium. Circulation 95: 1193–1200, 1997

    Google Scholar 

  39. Giasson E, Servant MJ, Meloche S: Cyclic AMP-mediated inhibition of angiotensin II-induced protein synthesis is associated with suppression of tyrosine phosphorylation signaling in vascular smooth muscle cells. J Biol Chem 272: 26879–26886, 1997

    Google Scholar 

  40. Ziegler D, Haxhiu MA, Kaan EC, Papp JG, Ernsberger P: Pharmacology of moxonidine, an I1-imidazoline receptor agonist. J Cardiovasc Pharmacol 27(suppl 3): S26–S37, 1996

    Google Scholar 

  41. Rupp H: Excess catecholamine syndrome. Pathophysiology and therapy. Ann NY Acad Sci 881: 430–444, 1999

    Google Scholar 

  42. Hayashi Y, Iijima K, Katada J, Kiso Y: Structure-activity relationship studies of chloromethyl ketone derivatives for selective human chymase inhibitors. Bioorg Med Chem Lett 10:199–201, 2000

    Google Scholar 

  43. Zimmerman BG, Kraft E: Blockade by saralasin of adrenergic potentiation induced by renin-angiotensin system. J Pharmacol Exp Ther 210: 101–105, 1979

    Google Scholar 

  44. Kaufman LJ, Vollmer RR: Endogenous angiotensin II facilitates sympathetically mediated hemodynamic responses in pithed rats. J Pharmacol Exp Ther 235: 128–134, 1985

    Google Scholar 

  45. Wong PC, Bernard R, Timmermans PB: Effect of blocking angiotensin II receptor subtype on rat sympathetic nerve function. Hypertension 19: 663–667, 1992

    Google Scholar 

  46. Brasch H, Sieroslawski L, Dominiak P: Angiotensin II increases norepinephrine release from atria by acting on angiotensin subtype 1 receptors. Hypertension 22: 699–704, 1993

    Google Scholar 

  47. Dendorfer A, Raasch W, Tempel K, Dominiak P: Interactions between the renin-angiotensin system (RAS) and the sympathetic system. Basic Res Cardiol 93(suppl 2): 24–29, 1998

    Google Scholar 

  48. Cox SL, Trendelenburg AU, Starke K: Prejunctional angiotensin receptors involved in the facilitation of noradrenaline release in mouse tissues. Br J Pharmacol 127: 1256–1262, 1999

    Google Scholar 

  49. Ohlstein EH, Gellai M, Brooks DP, Vickery L, Jugus J, Sulpizio A, Ruffolo RR Jr, Weinstock J, Edwards RM: The antihypertensive effect of the angiotensin II receptor antagonist DuP 753 may not be due solely to angiotensin II receptor antagonism. J Pharmacol Exp Ther 262: 595–601, 1992

    Google Scholar 

  50. Ohlstein EH, Brooks DP, Feuerstein GZ, Ruffolo RR, Jr: Inhibition of sympathetic outflow by the angiotensin II receptor antagonist, eprosartan, but not by losartan, valsartan or irbesartan: Relationship to differences in prejunctional angiotensin II receptor blockade. Pharmacology 55: 244–251, 1997

    Google Scholar 

  51. Rupp H, Maisch B: Radiotelemetric characterization of overweightassociated rises in blood pressure and heart rate. Am J Physiol 277: H1540–H1545, 1999

    Google Scholar 

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Rupp, H., Benkel, M. & Maisch, B. Control of cardiomyocyte gene expression as drug target. Mol Cell Biochem 212, 135–142 (2000). https://doi.org/10.1023/A:1007181626766

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