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Frontiers in Cardiovascular Health pp 177–194Cite as

Drug Development Based on Functional Genomics of Overloaded Cardiomyocytes: CPT 1 vs. PPARalpha Effects of Etomoxir

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Part of the book series: Progress in Experimental Cardiology ((PREC,volume 9))

Abstract

Heart failure remains a fatal disease with a constantly increasing incidence. Apart from an improved therapy of acute cardiac events, a main reason is seen in the increasing age of the population that frequently is accompanied with an inadequately treated hypertension leading to a chronic pressure overload of the heart. Heart failure is the final outcome of diseases such as hypertension, coronary heart disease, myocarditis, cardiomyopathies, heart valve disorders, cardiac gene defects, diabetes and sepsis. Hypertension and cardiac hypertrophy are present in approximately 90% of patients with heart failure (1). Also after myocardial infarction, an overload occurs in the non-infarcted area leading to an adverse remodelling and thus a further functional deterioration of ventricular function. Since at present no diagnostic measures are in general use for identifying early stages of heart failure, the disease is detected often very late and after symptoms are observed. The current standard therapy is targeted at preventing the further progression of heart failure, whereby the therapy is inadequate in many patients (1). The major drug target is activation of the neuroendocrine system resulting from an impaired cardiac performance. As is the case of an acute blood loss, activation of the sympathetic nervous system, the renin angiotensin-aldosterone-system (RAAS) and the endothelin and vasopressin system occurs when cardiac function becomes impaired.

The review part of the present study is based on Rupp and Maisch (2002) Herz 27:1–8

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References

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

    PubMed  CAS  Google Scholar 

  2. Remme WJ. 1998. Towards the better treatment of heart failure. Eur Heart J 19 Suppl L:L36–L42.

    PubMed  Google Scholar 

  3. Devereux RB, Roman MJ, Paranicas M, Lee ET, Welty TK, Fabsitz RR, Robbins D, Rhoades ER, Rodeheffer RJ, Cowan LD, Howard BV. 2001. A population-based assessment of left ventricular systolic dysfunction in middle-aged and older adults: The Strong Heart Study. Am Heart J 141:439–446.

    Article  PubMed  CAS  Google Scholar 

  4. Malik IS, BhatiaVK, Kooner JS. 2001. Cost effectiveness of ramipril treatment for cardiovascular risk reduction. Heart 85:539–543.

    CAS  Google Scholar 

  5. McDonagh TA, Robb SD, Murdoch DR, Morton JJ, Ford I, Morrison CE, Tunstall-Pedoe H, McMurray JJ, Dargie HJ. 1998. Biochemical detection of left-ventricular systolic dysfunction. Lancet 351:9–13.

    Article  PubMed  CAS  Google Scholar 

  6. Luchner A, Burnett JC, Jougasaki M, Hense HW, Heid IM, Muders F, Riegger GA, Schunkert H. 2000. Evaluation of brain natriuretic peptide as marker of left ventricular dysfunction and hypertrophy in the population. J Hypertens 18:1121–1128.

    Article  PubMed  CAS  Google Scholar 

  7. Stanton LW, Garrard LJ, Damm D, Garrick BL, Lam A, Kapoun AM, Zheng Q, Protter AA, Schreiner GF, White RT. 2000. Altered patterns of gene expression in response to myocardial infarction. Circ Res 86:939–945.

    Article  PubMed  CAS  Google Scholar 

  8. Kelly DP, Gordon JI, Alpers R, Strauss AW. 1989. The tissue-specific expression and developmental regulation of two nuclear genes encoding rat mitochondrial proteins. Medium chain acyl-CoA dehydrogenase and mitochondrial malate dehydrogenase. J Biol Chem 264:18921–18925.

    PubMed  CAS  Google Scholar 

  9. Sack MN, Rader TA, Park S, Bastin J, McCune SA, Kelly DP. 1996. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation 94:2837–2842.

    Article  PubMed  CAS  Google Scholar 

  10. Bishop SP, Altschuld RA. 1970. Increased glycolytic metabolism in cardiac hypertrophy and congestive failure. Am J Physiol 218:153–159.

    PubMed  CAS  Google Scholar 

  11. Taegtmeyer H, Overturf ML. 1988. Effects of moderate hypertension on cardiac function and metabolism in the rabbit. Hypertension 11:416–426.

    Article  PubMed  CAS  Google Scholar 

  12. Christe ME, Rodgers RL. 1994. Altered glucose and fatty acid oxidation in hearts of the spontaneously hypertensive rat. J Mol Cell Cardiol 26:1371–1375.

    Article  PubMed  CAS  Google Scholar 

  13. Feinendegen LE, Henrich MM, Kuikka JT, Thompson KH, Vester EG, Strauer B. 1995. Myocardial lipid turnover in dilated cardiomyopathy: a dual in vivo tracer approach. J Nucl Cardiol 2:42–52.

    Article  PubMed  CAS  Google Scholar 

  14. Sack MN, Disch DL, Rockman HA, Kelly DP. 1997. A role for Sp and nuclear receptor transcription factors in a cardiac hypertrophic growth program. Proc Natl Acad Sci USA 94:6438–6443.

    Article  PubMed  CAS  Google Scholar 

  15. Barger PM, Brandt JM, Leone TC, Weinheimer CJ, Kelly DP. 2000. Deactivation of peroxisome proliferator-activated receptor-alpha during cardiac hypertrophic growth. J Clin Invest 105:1723–1730.

    Article  PubMed  CAS  Google Scholar 

  16. Hamrell BB, Huber SA, Leslie KO. 1994. Reduced unloaded sarcomere shortening velocity and a shift to a slower myosin isoform in acute murine coxsackievirus myocarditis. Circ Res 75:462–472.

    Article  PubMed  CAS  Google Scholar 

  17. Hamrell BB, Huber SA, Leslie KO. 1995. Depressed unloaded sarcomere shortening velocity in acute murine coxsackievirus myocarditis: myocardial remodelling in the absence of necrosis or hypertrophy. Eur Heart J 16 Suppl O:31–35.

    Article  PubMed  Google Scholar 

  18. Taylor LA, Carthy CM, Yang D, Saad K, Wong D, Schreiner G, Stanton LW, McManus BM. 2000. Host gene regulation during coxsackievirus B3 infection in mice: assessment by microarrays. Circ Res 87:328–334.

    Article  PubMed  CAS  Google Scholar 

  19. Portilla D, Dai G, Peters JM, Gonzalez FJ, Crew MD, Proia AD. 2000. Etomoxir-induced PPARalpha-modulated enzymes protect during acute renal failure. Am J Physiol Renal Physiol 278:F667–F675.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  21. Rupp H, Vetter R. 2000. Sarcoplasmic reticulum function and carnitine palmitoyltransferase-1 inhibition during progression of heart failure. Br J Pharmacol 131:1748–1756.

    Article  PubMed  CAS  Google Scholar 

  22. Wang SQ, Song LS, Lakatta EG, Cheng H. 2001. Ca2+ signalling between single L-type Ca2+ channels and ryanodine receptors in heart cells. Nature 410:592–596.

    Article  PubMed  CAS  Google Scholar 

  23. Yue P, Long CS, Austin R, Chang KC, Simpson PC, Massie BM. 1998. Post-infarction heart failure in the rat is associated with distinct alterations in cardiac myocyte molecular phenotype. J Mol Cell Cardiol 30:1615–1630.

    Article  PubMed  CAS  Google Scholar 

  24. Nagai R, Zarain-Herzberg A, Brandl CJ, Fujii J, Tada M, MacLennan DH, Alpert NR, Periasamy M. 1989. Regulation of myocardial Ca2+-ATPase and phospholamban mRNA expression in response to pressure overload and thyroid hormone. Proc Natl Acad Sci U S A 86:2966–2970.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  26. Rupp H, Maisch B, Brilla CG. 1997. Schedule-induced psychological stress and molecular structures of cardiomyocytes. Am J Physiol 272:R776–R782.

    PubMed  CAS  Google Scholar 

  27. Rupp H, Benkel M, Maisch B. 2000. Control of cardiomyocyte gene expression as drug target. Mol Cell Biochem 212:135–142.

    Article  PubMed  CAS  Google Scholar 

  28. Kinugawa K, Minobe WA, Wood WM, Ridgway EC, Baxter JD, Ribeiro RC, Tawadrous MF, Lowes BA, Long CS, Bristow MR. 2001. Signaling Pathways Responsible for Fetal Gene Induction in the Failing Human Heart: Evidence for Altered Thyroid Hormone Receptor Gene Expression. Circulation 103:1089–1094.

    Article  PubMed  CAS  Google Scholar 

  29. Rupp H, Elimban V, Dhalla NS. 1992. Modification of subcellular organelles in pressure-overloaded heart by etomoxir, a carnitine palmitoyltransferase I inhibitor. FASEB J 6:2349–2353.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  31. Rupp H, Schulze W, Vetter R. 1995. Dietary medium-chain triglycerides can prevent changes in myosin and SR due to CPT-1 inhibition by etomoxir. Am J Physiol 269:R630–R640.

    PubMed  CAS  Google Scholar 

  32. Vetter R, Rupp H. 1994. CPT-1 inhibition by etomoxir has a chamber-related action on cardiac sarcoplasmic reticulum and isomyosins. Am J Physiol 267:H2091–H2099.

    PubMed  CAS  Google Scholar 

  33. Forman BM, Chen J, Evans RM. 1997. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci U S A 94:4312–4317.

    Article  PubMed  CAS  Google Scholar 

  34. Rupp H. 1989. Differential effect of physical exercise routines on ventricular myosin and peripheral catecholamine stores in normotensive and spontaneously hypertensive rats. Circ Res 65: 370–377.

    Article  PubMed  CAS  Google Scholar 

  35. Vetter R, Kott M, Rupp H. 1995. Differential influences of carnitine palmitoyltransferase-1 inhibition and hyperthyroidism on cardiac growth and sarcoplasmic reticulum phosphorylation. Eur Heart J 16 Suppl C:15–19.

    Article  PubMed  CAS  Google Scholar 

  36. Mascaro C, Acosta E, Ortiz JA, Marrero PF, Hegardt FG, Haro D. 1998. Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor. J Biol Chem 273:8560–8563.

    Article  PubMed  CAS  Google Scholar 

  37. Brandt JM, Djouadi F, Kelly DP. 1998. 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.

    Article  PubMed  CAS  Google Scholar 

  38. Barger PM, Kelly DP. 2000. PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc Med 10:238–245.

    Article  PubMed  CAS  Google Scholar 

  39. Lee KA, Vork MM, De Vries JE, Willemsen PH, Glatz JF, Reneman RS, van derVusse GJ, van Bilsen M. 2000. Long-chain fatty acid-induced changes in gene expression in neonatal cardiac myocytes. J Lipid Res 41:41–47.

    PubMed  Google Scholar 

  40. van Bilsen M, van der Vusse GJ, Reneman RS. 1998. Transcriptional regulation of metabolic processes: implications for cardiac metabolism. Pflugers Arch 437:2–14.

    Article  PubMed  Google Scholar 

  41. Bishop-Bailey D. 2000. Peroxisome proliferator-activated receptors in the cardiovascular system. Br J Pharmacol 129:823–834.

    Article  PubMed  CAS  Google Scholar 

  42. Djouadi F, Brandt JM, Weinheimer CJ, Leone TC, Gonzalez FJ, Kelly DP. 1999. The role of the peroxisome proliferator-activated receptor alpha (PPAR alpha) in the control of cardiac lipid metabolism. Prostaglandins Leukot Essent Fatty Acids 60:339–343.

    Article  PubMed  CAS  Google Scholar 

  43. Kanda H, Nohara R, Hasegawa K, Kishimoto C, Sasayama S. 2002. A nuclear complex containing PPARalpha/RXRalpha is markedly downregulated in the hypertrophied rat left ventricular myocardium with normal systolic function. Heart Vessels 2000;15(4):191–196 15:191–196.

    Article  Google Scholar 

  44. Zarain-Herzberg A, Rupp H. 2002. Therapeutic potential of CPT I inhibitors: cardiac gene transcription as a target. Expert Opin Investig Drugs 11:345–356.

    Article  PubMed  CAS  Google Scholar 

  45. Barger PM, Browning AC, Garner AN, Kelly DP. 2001. p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha: a potential role in the cardiac metabolic stress response. J Biol Chem 276:44495–44501.

    Article  PubMed  CAS  Google Scholar 

  46. Qi M, Shannon TR, Euler DE, Bers DM, Samarel AM. 1997. Downregulation of sarcoplasmic reticulum Ca(2+)-ATPase during progression of left ventricular hypertrophy. Am J Physiol 272:H2416–H2424.

    PubMed  CAS  Google Scholar 

  47. Ribadeau Dumas A, Wisnewsky C, Boheler KR, Ter Keurs H, Fiszman MY, Schwartz K. 1997. The sarco(endo)plasmic reticulum Ca(2+)-ATPase gene is regulated at the transcriptional level during compensated left ventricular hypertrophy in the rat. C R Acad Sci III 320:963–969.

    Article  PubMed  CAS  Google Scholar 

  48. Takizawa T, Arai M, Yoguchi A, Tomaru K, Kurabayashi M, Nagai R. 1999. Transcription of the SERCA2 gene is decreased in pressure-overloaded hearts: A study using in vivo direct gene transfer into living myocardium. J Mol Cell Cardiol 31:2167–2174.

    Article  PubMed  CAS  Google Scholar 

  49. Aoyagi T, Yonekura K, Eto Y, Matsumoto A, Yokoyama I, Sugiura S, Momomura S, Hirata Y, Baker DL, Periasamy M. 1999. The sarcoplasmic reticulum Ca2+-ATPase (SERCA2) gene promoter activity is decreased in response to severe left ventricular pressure-overload hypertrophy in rat hearts. J Mol Cell Cardiol 31:919–926.

    Article  PubMed  CAS  Google Scholar 

  50. Ojamaa K, Samarel AM, Klein I. 1995. Identification of a contractile-responsive element in the cardiac alpha-myosin heavy chain gene. J Biol Chem 270:31276–31281.

    Article  PubMed  CAS  Google Scholar 

  51. Xiao Q, Ojamaa K. 1998. Regulation of cardiac alpha-myosin heavy chain gene transcription by a contractile-responsive E-box binding protein. J Mol Cell Cardiol 30:87–95.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  54. Schmidt-Schweda S, Holubarsch C. 2000. First clinical trial with etomoxir in patients with chronic congestive heart failure. Clin Sci (Colch) 99:27–35.

    Article  CAS  Google Scholar 

  55. Steiner S, Wahl D, Mangold BL, Robison R, Raymackers J, Meheus L, Anderson NL, Cordier A. 1996. Induction of the adipose differentiation-related protein in liver of etomoxir-treated rats. Biochem Biophys Res Commun 218:777–782.

    Article  PubMed  CAS  Google Scholar 

  56. Bristow M. 2000. Etomoxir: a new approach to treatment of chronic heart failure. Lancet 356: 1621–1622.

    Article  PubMed  CAS  Google Scholar 

  57. Corr PB, Creer MH, Yamada KA, Saffitz JE, Sobel BE. 1989. Prophylaxis of early ventricular fibrillation by inhibition of acylcarnitine accumulation. J Clin Invest 83:927–936.

    Article  PubMed  CAS  Google Scholar 

  58. Lopaschuk GD, Wall SR, Olley PM, Davies NJ. 1988. Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine. Circ Res 63:1036–1043.

    Article  PubMed  CAS  Google Scholar 

  59. Lopaschuk GD, McNeil GF, McVeigh JJ. 1989. Glucose oxidation is stimulated in reperfused ischemic hearts with the carnitine palmitoyltransferase 1 inhibitor, Etomoxir. Mol Cell Biochem 88:175–179.

    Article  PubMed  CAS  Google Scholar 

  60. Lopaschuk GD, Spafford M. 1989. Response of isolated working hearts to fatty acids and carnitine palmitoyltransferase I inhibition during reduction of coronary flow in acutely and chronically diabetic rats. Circ Res 65:378–387.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  64. Jacob R, Brandie M, Dierberger B, Rupp H. 1991. Functional consequences of cardiac hypertrophy and dilatation. Basic Res Cardiol 86 Suppl 1:113–130.

    PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  66. Harada K, Komuro I, Shiojima I, Hayashi D, Kudoh S, Mizuno T, Kijima K, Matsubara H, Sugaya T, Murakami K, Yazaki Y. 1998. Pressure overload induces cardiac hypertrophy in angiotensin II type 1A receptor knockout mice. Circulation 97:1952–1959.

    Article  PubMed  CAS  Google Scholar 

  67. Turcani M, Rupp H. 2000. Heart failure development in rats with ascending aortic constriction and angiotensin-converting enzyme inhibition. Br J Pharmacol 130:1671–1677.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology, Philipps University of Marburg, Karl-von-Frisch-Str. 1, 35033, Marburg, Germany

    Heinz Rupp Ph.D. & Bernhard Maisch

  2. Laboratorio de Biología Molecular, Departamento de Bioquímica, Facultad de Mediana, Universidad Nacional Autónoma de México, México D. F., México

    Angel Zarain-Herzberg

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  1. Heinz Rupp Ph.D.
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  2. Angel Zarain-Herzberg
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  3. Bernhard Maisch
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Correspondence to Heinz Rupp Ph.D. .

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Editors and Affiliations

  1. Institute of Cardiovascular Sciences St. Boniface General Hospital Research Centre Faculty of Medicine, University of Manitoba, Winnipeg, Canada

    Naranjan S. Dhalla PhD, MD (Hon), DSc (Hon) (Distinguished Professor and Director), H. Ivan Berkowitz MBA (Consultant) & Pawan K. Singal PhD, DSc (Professor) (Distinguished Professor and Director),  (Consultant) &  (Professor)

  2. Institute of Circulatory & Respiratory Health, Canadian Institutes of Health Research, Vancouver, Canada

    Arun Chockalingam PhD (Assistant Director) (Assistant Director)

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Rupp, H., Zarain-Herzberg, A., Maisch, B. (2003). Drug Development Based on Functional Genomics of Overloaded Cardiomyocytes: CPT 1 vs. PPARalpha Effects of Etomoxir. In: Dhalla, N.S., Chockalingam, A., Berkowitz, H.I., Singal, P.K. (eds) Frontiers in Cardiovascular Health. Progress in Experimental Cardiology, vol 9. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0455-9_14

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