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Journal of Cardiovascular Translational Research

Published in:

01-06-2009

Chronic Treatment with Clenbuterol Modulates Endothelial Progenitor Cells and Circulating Factors in a Murine Model of Cardiomyopathy

Authors: James E. Rider, Sean P. Polster, Sangjin Lee, Nathan J. Charles, Neeta Adhikari, Ami Mariash, George Tadros, Jenna Stangland, Ryszard T. Smolenski, Cesare M Terracciano, Paul J.R. Barton, Emma J. Birks, Magdi H. Yacoub, Leslie W. Miller, Jennifer L. Hall

Published in: Journal of Cardiovascular Translational Research | Issue 2/2009

Abstract

The purpose of this study was to determine the effects of chronic treatment with the beta 2 adrenergic receptor agonist clenbuterol on endothelial progenitor cells (EPC) in a well-characterized model of heart failure, the muscle LIM protein knockout (MLP^−/−) mouse. MLP^−/− mice were treated daily with clenbuterol (2 mg/kg) or saline subcutaneously for 6 weeks. Clenbuterol led to a 30% increase in CD31⁺ cells in the bone marrow of MLP^−/− heart failure mice (p < 0.004). Clenbuterol did not improve ejection fraction. Clenbuterol treatment in MLP^−/− mice was associated with significant changes in the following circulating factors: tissue inhibitor of metalloproteinase-type 1, leukemia inhibitory factor 1, C-reactive protein, apolipoprotein A1, fibroblast growth factor 2, serum glutamic oxaloacetic transaminase, macrophage-derived chemokine, and monocyte chemoattractant protein-3. Clenbuterol treatment in the MLP^−/− model of heart failure did not rescue heart function, yet did increase CD31⁺ cells in the bone marrow. This is the first evidence that a beta 2 agonist increases EPC proliferation in the bone marrow in a preclinical model of heart failure.

Antoons, G., Vangheluwe, P., Volders, P. G., Bito, V., Holemans, P., Ceci, M., Wuytack, F., Caroni, P., Mubagwa, K., & Sipido, K. R. (2006). Increased phospholamban phosphorylation limits the force-frequency response in the MLP^−/− mouse with heart failure. Journal of Molecular and Cellular Cardiology, 40, 350–360.PubMedCrossRef

Arber, S., Hunter, J. J., Ross Jr., J., Hongo, M., Sansig, G., Borg, J., Perriard, J. C., Chien, K. R., & Caroni, P. (1997). MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure. Cell, 88, 393–403.PubMedCrossRef

Badea, C. T., Hedlund, L. W., Mackel, J. F., Mao, L., Rockman, H. A., & Johnson, G. A. (2007). Cardiac micro-computed tomography for morphological and functional phenotyping of muscle LIM protein null mice. Molecular Imaging, 6, 261–268.PubMed

Barton, P. J. B. E., Felkin, L. E., Cullen, M. E., Koban, M. U., & Yacoub, M. H. (2003). Increased expression of extracellular matrix regulators TIMP1 and MMP1 in deteriorating heart failure. Journal of Heart and Lung Transplantation, 22, 738–744.PubMedCrossRef

Birks, E. J., Hall, J. L., Barton, P. J., Grindle, S., Latif, N., Hardy, J. P., Rider, J. E., Banner, N. R., Khaghani, A., Miller, L. W., & Yacoub, M. H. (2005). Gene profiling changes in cytoskeletal proteins during clinical recovery after left ventricular-assist device support. Circulation, 112, I57–64.PubMed

Birks, E. J., Tansley, P. D., Hardy, J., George, R. S., Bowles, C. T., Burke, M., Banner, N. R., Khaghani, A., & Yacoub, M. H. (2006). Left ventricular assist device and drug therapy for the reversal of heart failure. The New England Journal of Medicine, 355, 1873–1884.PubMedCrossRef

Cottler-Fox, M. H., Lapidot, T., Petit, I., Kollet, O., DiPersio, J. F., Link, D., & Devine, S. (2003). Stem cell mobilization. Hematology, 2003, 419–437.CrossRef

Ehler, E., Horowits, R., Zuppinger, C., Price, R. L., Perriard, E., Leu, M., Caroni, P., Sussman, M., Eppenberger, H. M., & Perriard, J. C. (2001). Alterations at the intercalated disk associated with the absence of muscle LIM protein. The Journal of Cell Biology, 153, 763–772.PubMedCrossRef

Esposito, G., Santana, L. F., Dilly, K., Cruz, J. D., Mao, L., Lederer, W. J., & Rockman, H. A. (2000). Cellular and functional defects in a mouse model of heart failure. American Journal of Physiology Heart and Circulatory Physiology, 279, H3101–H3112.PubMed

10.

Fleige, S., Walf, V., Huch, S., Prgomet, C., Sehm, J., & Pfaffl, M. W. (2006). Comparison of relative mRNA quantification models and the impact of RNA integrity in quantitative real-time RT-PCR. Biotechnology Letters, 28, 1601–1613.PubMedCrossRef

11.

George, I., Xydas, S., Mancini, D. M., Lamanca, J., DiTullio, M., Marboe, C. C., Shane, E., Schulman, A. R., Colley, P. M., Petrilli, C. M., Naka, Y., Oz, M. C., & Maybaum, S. (2006). Effect of clenbuterol on cardiac and skeletal muscle function during left ventricular assist device support. Journal of Heart and Lung Transplantation, 25, 1084–1090.PubMedCrossRef

12.

Hall, J. L., Birks, E. J., Grindle, S., Cullen, M. E., Barton, P. J., Rider, J. E., Lee, S., Harwalker, S., Mariash, A., Adhikari, N., Charles, N. J., Felkin, L. E., Polster, S., George, R. S., Miller, L. W., & Yacoub, M. H. (2007). Molecular signature of recovery following combination left ventricular assist device (LVAD) support and pharmacologic therapy. European Heart Journal, 28, 613–627.PubMedCrossRef

13.

Heineke, J., Ruetten, H., Willenbockel, C., Gross, S. C., Naguib, M., Schaefer, A., Kempf, T., Hilfiker-Kleiner, D., Caroni, P., Kraft, T., Kaiser, R. A., Molkentin, J. D., Drexler, H., & Wollert, K. C. (2005). Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc. Proceedings of the National Academy of Sciences of the United States of America, 102, 1655–1660.PubMedCrossRef

14.

Hill, J. M., Zalos, G., Halcox, J. P., Schenke, W. H., Waclawiw, M. A., Quyyumi, A. A., & Finkel, T. (2003). Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. The New England Journal of Medicine, 348, 593–600.PubMedCrossRef

15.

Hoit, B. D. (2006). Excitation-contraction coupling in the MLP knockout mouse. Journal of Molecular and Cellular Cardiology, 40, 335–338.PubMedCrossRef

16.

Hongo, M., Ryoke, T., Schoenfeld, J., Hunter, J., Dalton, N., Clark, R., Lowe, D., Chien, K., & Ross, J. Jr. (2000). Effects of growth hormone on cardiac dysfunction and gene expression in genetic murine dilated cardiomyopathy. Basic Research in Cardiology, 95, 431–441.PubMedCrossRef

17.

Izeboud, C. A. H. K., Grootendorst, A. F., Nijmeijer, S. M., van Miert, A. S., Witkamp, R. R., & Rodenburg, R. J. (2004). Endotoxin-induced liver damage in rats is minimized by beta 2-adrenoceptor stimulation. Inflammation Research, 53, 93–99.PubMedCrossRef

18.

Jougasaki, M., Leskinen, H., Larsen, A. M., Cataliotti, A., Chen, H. H., & Burnett, J. C. Jr. (2003). Leukemia inhibitory factor is augmented in the heart in experimental heart failure. European Journal of Heart Failure, 5, 137–145.PubMedCrossRef

19.

Katayama, Y., Battista, M., Kao, W. M., Hidalgo, A., Peired, A. J., Thomas, S. A., & Frenette, P. S. (2006). Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell, 124, 407–421.PubMedCrossRef

20.

Kissel, C. K., Lehmann, R., Assmus, B., Aicher, A., Honold, J., Fischer-Rasokat, U., Heeschen, C., Spyridopoulos, I., Dimmeler, S., & Zeiher, A. M. (2007). Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with postinfarction heart failure. Journal of the American College of Cardiology, 49, 2341–2349.PubMedCrossRef

21.

Knoll, R., Hoshijima, M., Hoffman, H. M., Person, V., Lorenzen-Schmidt, I., Bang, M. L., Hayashi, T., Shiga, N., Yasukawa, H., Schaper, W., McKenna, W., Yokoyama, M., Schork, N. J., Omens, J. H., McCulloch, A. D., Kimura, A., Gregorio, C. C., Poller, W., Schaper, J., Schultheiss, H. P., & Chien, K. R. (2002). The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell, 111, 943–955.PubMedCrossRef

22.

Lorenzen-Schmidt, I., Stuyvers, B. D., ter Keurs, H. E., Date, M. O., Hoshijima, M., Chien, K. R., McCulloch, A. D., & Omens, J. H. (2005). Young MLP deficient mice show diastolic .dysfunction before the onset of dilated cardiomyopathy. Journal of Molecular and Cellular Cardiology, 39, 241–250.PubMedCrossRef

23.

Panteghini., M. (1990). Aspartate aminotransferase isoenzymes. Clinical Biochemistry, 23, 311–319.PubMedCrossRef

24.

McKie, P. M. B. J. J. (2005). B-type natriuretic peptide as a biomarker beyond heart failure: speculations and opportunities. Mayo Clinic Proceedings, 80, 1029–1036.PubMedCrossRef

25.

Minamisawa, S., Hoshijima, M., Chu, G., Ward, C. A., Frank, K., Gu, Y., Martone, M. E., Wang, Y., Ross Jr., J., Kranias, E. G., Giles, W. R., & Chien, K. R. (1999). Chronic phospholamban-sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy. Cell, 99, 313–322.PubMedCrossRef

26.

Omens, J. H., Usyk, T. P., Li, Z., & McCulloch, A. D. (2002). Muscle LIM protein deficiency leads to alterations in passive ventricular mechanics. American Journal of Physiology, 282, H680–H687.PubMed

27.

Petrou, M., Wynne, D. G., Boheler, K. R., & Yacoub, M. H. (1995). Clenbuterol induces hypertrophy of the latissimus dorsi muscle and heart in the rat with molecular and phenotypic changes. Circulation, 92, II483–II489.PubMed

28.

Rockman, H. A. C. K., Choi, D. J., Iaccarino, G., Hunter, J. J., Ross Jr., J., Lefkowitz, R. J., & Koch, W. J. (1998). Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proceedings of the National Academy of Sciences of the United States of America, 95, 7000–7005.PubMedCrossRef

29.

Schmidt-Lucke, C., Rossig, L., Fichtlscherer, S., Vasa, M., Britten, M., Kamper, U., Dimmeler, S., & Zeiher, A. M. (2005). Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation, 111, 2981–2987.PubMedCrossRef

30.

Soppa, G. K., Lee, J., Stagg, M. A., Felkin, L. E., Barton, P. J., Siedlecka, U., Youssef, S., Yacoub, M. H., & Terracciano, C. M. (2008). Role and possible mechanisms of clenbuterol in enhancing reverse remodelling during mechanical unloading in murine heart failure. Cardiovascular Research, 77, 695–706.PubMedCrossRef

31.

Soppa, G. K. S. R., Latif, N., Yuen, A. H., Malik, A., Karbowska, J., Kochan, Z., Terracciano, C. M., & Yacoub, M. H. (2005). Effects of chronic administration of clenbuterol on function and metabolism of adult rat cardiac muscle. American Journal of Physiology, 288, H1468–H1476.PubMed

32.

Spiegel, A. Shivtiel, S., Alexander, K., Aya, L., Neta, N., Polina, G., Yaara, A., Igor, R., Hardan, I., Herzel, B., Arnon, N., Menachem, R., & Tsvee, L. (2007). Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling. Nature Immunology, 8, 1123–1131.PubMedCrossRef

33.

Su, Z., Yao, A., Zubair, I., Sugishita, K., Ritter, M., Li, F., Hunter, J. J., Chien, K. R., & Barry, W. H. (2001). Effects of deletion of muscle LIM protein on myocyte function. American Journal of Physiology, 280, H2665–H2673.PubMed

34.

Sundstrom, J. E. J., Benjamin, E. J., Levy, D., Larson, M. G., Sawyer, D. B., Siwik, D. A., Colucci, W. S., Wilson, P. W. F., & Vasan, R. S. (2004). Relations of plasma total TIMP-1 levels to cardiovascular risk factors and echocardiographic measures: the Framingham heart study. European Heart Journal, 25, 1509–1516.PubMedCrossRef

35.

Tsuruda, T., Boerrigter, G., Huntley, B. K., Noser, J. A., Cataliotti, A., Costello-Boerrigter, L. C., Chen, H. H., & Burnett Jr., J. C. (2002). Brain natriuretic Peptide is produced in cardiac fibroblasts and induces matrix metalloproteinases. Circulation Research, 91, 1127–1134.PubMedCrossRef

36.

Valgimigli, M., Rigolin, G. M., Fucili, A., Porta, M. D., Soukhomovskaia, O., Malagutti, P., Bugli, A. M., Bragotti, L. Z., Francolini, G., Mauro, E., Castoldi, G., & Ferrari, R. (2004). CD34+ and endothelial progenitor cells in patients with various degrees of congestive heart failure. Circulation, 110, 1209–1212.PubMedCrossRef

37.

van den Bosch, B. J., van den Burg, C. M., Schoonderwoerd, K., Lindsey, P. J., Scholte, H. R., de Coo, R. F., van Rooij, E., Rockman, H. A., Doevendans, P. A., & Smeets, H. J. (2005). Regional absence of mitochondria causing energy depletion in the myocardium of muscle LIM protein knockout mice. Cardiovascular Research, 65, 411–418.PubMedCrossRef

38.

Vasa, M., Fichtlscherer, S., Aicher, A., Adler, K., Urbich, C., Martin, H., Zeiher, A. M., & Dimmeler, S. (2001). Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circulation Research, 89, E1–E7.PubMedCrossRef

39.

Wang, X. X. Y., Mou, Y., Zhao, Y., Blankesteijn, W. M., & Hall, J. L. (2002). A role for the beta-catenin/T-cell factor signaling cascade in vascular remodeling. Circulation Research, 90, 340–347.PubMedCrossRef

40.

Werner, N., Kosiol, S., Schiegl, T., Ahlers, P., Walenta, K., Link, A., Bohm, M., & Nickenig, G. (2005). Circulating endothelial progenitor cells and cardiovascular outcomes. The New England Journal of Medicine, 353, 999–1007.PubMedCrossRef

41.

Wong, K. B. K., Bishop, J., Petrou, M., & Yacoub, M. H. (1998). Clenbuterol induces cardiac hypertrophy with normal functional, morphological and molecular features. Cardiovascular Research, 37, 115–122.PubMedCrossRef

42.

Wong, K., Boheler, K. R., Petrou, M., & Yacoub, M. H. (1997). Pharmacological modulation of pressure-overload cardiac hypertrophy: changes in ventricular function, extracellular matrix, and gene expression. Circulation, 96, 2239–2246.PubMed

43.

Wright, D. E., Cheshier, S. H., Wagers, A. J., Randall, T. D., Christensen, J. L., & Weissman, I. L. (2001). Cyclophosphamide/granulocyte colony-stimulating factor causes selective mobilization of bone marrow hematopoietic stem cells into the blood after M phase of the cell cycle. Blood, 97, 2278–2285.PubMedCrossRef

44.

Yuen, A. H., Yacoub, M. H., & Smolenski, R. T. (2005). Determination of clenbuterol concentration in human blood using liquid chromatography with electrospray/ion-trap tandem mass spectrometry. Rapid Commun Mass Spectrom, 19, 3603–3606.PubMedCrossRef

45.

Zolk, O., Caroni, P., & Bohm, M. (2000). Decreased expression of the cardiac LIM domain protein MLP in chronic human heart failure. Circulation, 101, 2674–2677.PubMed

Title: Chronic Treatment with Clenbuterol Modulates Endothelial Progenitor Cells and Circulating Factors in a Murine Model of Cardiomyopathy
Authors: James E. Rider
Sean P. Polster
Sangjin Lee
Nathan J. Charles
Neeta Adhikari
Ami Mariash
George Tadros
Jenna Stangland
Ryszard T. Smolenski
Cesare M Terracciano
Paul J.R. Barton
Emma J. Birks
Magdi H. Yacoub
Leslie W. Miller
Jennifer L. Hall
Publication date: 01-06-2009
Publisher: Springer US
Published in: Journal of Cardiovascular Translational Research / Issue 2/2009
Print ISSN: 1937-5387
Electronic ISSN: 1937-5395
DOI: https://doi.org/10.1007/s12265-009-9089-6

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Chronic Treatment with Clenbuterol Modulates Endothelial Progenitor Cells and Circulating Factors in a Murine Model of Cardiomyopathy

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