The Contractile Protein Myosin, and Human Heart Failure
The physiological significance of the two unique cardiac myosin heavy chain (MHC) isoforms, alpha and beta has been appreciated for almost 40 years. In human heart failure, there are now accumulated data suggesting that these isoforms are modulated prior to, and during disease development. Recently, Leinwand and Bristow made the surprising discovery that human ventricular myosin heavy chain (MHC) is not made up only of the beta isoform, but also contains 7-10% of alpha-MHC. Furthermore, they and others have shown that alpha-MHC is down regulated in heart failure patients, and propose that small amounts of alpha-MHC have a disproportionate, strongly beneficial effect on hearts undergoing stress. The lab is focusing on the structure-function relationships of the cardiac contractile apparatus with the goal of creating defined animal models that are relevant to human cardiovascular disease. The central hypothesis is that MHC isoform switching during cardiovascular disease and heart failure impacts directly on the developing pathology and therefore is a potential therapeutic target. Transgenic (TG) and gene-targeted animal models have been and continue to be immensely valuable in unraveling mechanisms that underlie cardiovascular disease. However, they have been and continue to be limited largely to the mouse. The mouse is not a suitable model with which to test our hypothesis as its ventricles already express alpha-MHC. Thus we will now extend these models to the rabbit. The short-term goal is to test the hypothesis that alpha-MHC in the large(r) animal ventricle is innocuous under normal conditions and beneficial when the heart is stressed. As is the case for the human, the rabbit ventricle normally contains a very high (>95%) proportion of beta-MHC. Using cardiac-specific transgenesis in the rabbit heart we will vary the amount of alpha-MHC in the ventricle, and test whether the protein is cardioprotective when the heart is challenged. The experiments proposed herein will provide direct and unambiguous data concerning the role the different cardiac MHC isoforms can play in either exacerbating or blunting the pathology that leads to heart failure.
Related Publications
Krenz, M., Sadayappan, S., Osinska, H. E., Henry, J. A., Beck, S., Warshaw,D. M., Robbins, J. (2007) Distribution and structure-function relationship of myosin heavy chain isoforms in the adult mouse heart. J. Biol. Chem. 282:24057-24064
Sadayappan, S., Finley, N., Howarth, J. W., Osinska, H., Klevitsky, R., Lorenz, J. N., Rosevear, P. R., J. G., Robbins, J. (2008) Role of the acidic N¹-Region of cardiac troponin I in regulating myocardial function. FASEB Journal (in press)
Pinz, I., Robbins, J., Benjamin, I. J., Ingwall, J. (2008) Unmasking different mechanical and energetic roles for the small heat shock proteins CryAB and HSPB2 using genetically modified mouse hearts. FASEB J. 22:84-92
Hambleton, M., York, A., Sargent, M. A., Kaiser, R. A., Lorenz, J. N.,Robbins, J., Molkentin, J.D. (2007) Inducible and myocyte-specific inhibition of PKCa enhances cardiac contractility and protects against infarction-induced heart failure. Am. J. Physiol. Heart Circ. Physiol. 293: H3768-H3771
Nagyama, T., Takimoto, E., Sadayappan, S., Mudd, J. O., Seidman, J. G., Robbins, J., Kass, D. A. (2007) PKA-phosphorylation dependent and independent regulation of in vivo contraction/relaxation kinetics by myosin binding protein C. Circulation 116: 2399-2408
Diwan, A., Krenz, M., Sayed, F. M., Wanasapura, J., Ren, X., Matkovich, S.J., Koesters, A. G., Li, H., Kirshenbaum, L. A., Robbins, J., Jones, W. K.,Dorn, G. W. II (2007) Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of bnip3 restrains post-infarction remodeling. J. Clin.Invest. 117: 2825-2833
Oka, T., Xu, J., Kaiser, R. A., Melendez, J., Hambleton, M., Sargent, M. A,,Lorts, A., Brunskill, E. W., Dorn, G. W., 2nd, Conway, S. J., Aronow, B. J.,Robbins, J., Molkentin, J. D. (2007) Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling. Circ. Res. 101: 313-321
Hsieh, P. C. H., Davis, M. E., MacGillivray, C., Gannon, J., Molkentin, J.D., Robbins, J., Lee, R. T. (2007) Evidence that stem cells refresh adult mammalian cardiomyocytes following injury: A genetic fate-mapping study. Nature Med. 13, 970-974
Yasuda, S-I., Coutu, P., Sadayappan, S., Robbins, J. Metzger, J. M. (2007) Cardiac transgenic and gene transfer strategies converge to support a dominant effect of troponin I in regulating relaxation in cardiac myocytes. Circ Res. 101: 377-386.
Nakayama, H., Chen, X., Baines, C. P., Klevitsky, R., Zhang, L, Zhang, H.,Jaleel, N., Chua, B. H. L., Hewett, T. E., Robbins, J., Houser, S. R., Molkentin, J. D. (2007) Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. J Clin. Invest. 117,2123-2132
Galvez, A. S., Diwan, A., Odley, A. M., Hahn, H. S., Osinska, H., Melendez,J. G., Robbins, J., Lynch, R. A., Marreez, Y., Dorn, G. W. (2007). Cardiomyocyte degeneration with calpain deficiency reveals a critical role in protein homeostasis. Circ. Res. 100, 1071-1078
Hoyer, K., Krenz, M., Robbins, J., Ingwall, J. S. (2007) Shifts in the myosin heavy chain isozymes in the murine heart result in increased energy efficiency. J. Mol. Cell. Cardiol. 42, 214-221
Hoyer K, Krenz M, Robbins J, Ingwall JS. (2007) Shifts in the myosin heavy chain isozymes in the murine heart result in increased energy efficiency. J Mol Cell Cardiol 42, 214-221
Yutzey KE, Robbins J. (2007) Principles of genetic murine models for cardiac disease. Circulation 115: 792-799.
Sadayappan S, Osinska H, Klevitsky R, Lorenz JN, Sargent M, Molkentin JD, Seidman CE, Seidman JG, Robbins J. (2006) Cardiac myosin binding protein-C phosphorylation is cardioprotective. Proc Natl Acad Sci, USA 103:16918-16923
Dias FA, Walker LA, Arteaga GM, Walker JS, Vijayan K, Pena JR, Ke Y, Fogaca RT, Sanbe A, Robbins J, Wolska BM. (2006) The effect of myosin regulatory light chain phosphorylation on the frequency-dependent regulation of cardiac function. J Mol Cell Cardiol 41: 330-339
Sadayappan S, Gulick J, Osinska H, Martin LA, Hahn HS, Dorn GW II, Klevitsky R, Seidman CE, Seidman JG, Robbins J. (2005) Cardiac myosin binding protein-C phosphorylation and cardiac function. Circ Res 97: 1156-1163
Miller MS, Palmer BM, Ruch S, Murray LA, Farman GP, Wang Y, Robbins J, Irving TC, Maughan DW. (2005) The essential light chain N-terminal extension alters force and fiber kinetics in mouse cardiac muscle. J Biol Chem 280: 34427-34434
Gulick J, Robbins J. (2005) Inducible cardiac-specific transgenesis. Current Protocols in Molecular Biology Unit 23.12
Sanbe A, James J, Tuzcu V, Nas S, Martin L, Gulick J, Osinska H, Sakthivel S, Klevitsky R, Ginsburg KS, Bers DM, Zinman B, Lakatta EG, Robbins J. (2005) Transgenic rabbit model for human troponin I-based hypertrophic cardiomyopathy. Circulation 111:2330-8.
James J, Martin L, Krenz M, Quatman C, Jones F, Klevitsky R, Gulick J, Robbins J. (2005) Forced expression of alpha-myosin heavy chain in the rabbit ventricle results in cardioprotection under cardiomyopathic conditions. Circulation 111:2339-46.
Sadayappan S, Gulick J, Osinska H, Martin LA, Hahn HS, Dorn GW, 2nd, Klevitsky R, Seidman CE, Seidman JG, Robbins J. (2005) Cardiac myosin-binding protein-C phosphorylation and cardiac function. Circ Res 97:1156-63.
Gulick J, Robbins J. (2005) Inducible cardiac-specific transgenesis. Current Protocols in Molecular Biology. Unit 23.12
Krenz M, Robbins J. (2004) Impact of β-myosin heavy chain expression on cardiac function during stress. J Am Coll Cardiol 44:2390-7.
Sakthivel, S., Finley, N. L., Rosevear, P. R., Lorenz, J. N., Gulick, J., Kim, S., VanBuren, P., Martin, L. A., Robbins, J. (2004) In vivo and in vitro analysis of cardiac troponin I phosphorylation. J. Biol. Chem. 280: 703-714
Syed, F., Odley, A., Hahn, H. S., Brunskill, E. W., Lynch, R. A., Marreez, Y., Robbins, J., Dorn, G. W., II (2004) Physiological growth synergizes with pathological genes in experimental cardiomyopathy. Circ Res. 95:1200-1206
Robbins, J. (2004) Genetic modification of the heart: exploring necessity and sufficiency in the past 10 years. J. Mol. Cell. Cardiol. 6(5):643-52
Braz, J., Gregory, K., Pathak, A., Zhao, W., Sahin, B., Klevitsky, R., Kimball, T., Lorenz, J., Nairn, A., Liggett, S., Bodi, I., Wang, S., Schwartz, A., Lakatta, E., DePaoli, A., Robbins, J., Hewett, T., Bibb, J., Westfall, M., Kranias, E., Molkentin, J. D. (2004) PKCα regulates cardiac contractility and propensity towards heart failure. Nature New Medicine. 10:248-254.
Nakayama, M., Yan, X., Price, R.L., Borg, T.K., Ito, K., Sanbe, A., Robbins, J. Lorell, B.H. (2004) Chronic ventricular myocyte specific overexpression of angiotensin ii type 2 receptor results in intrinsic myocyte contractile dysfunction. Am J Physiol Heart Circ Physiol. 285:H2179-2187
Krenz, M., Sanbe, A., Bouyer-Dalloz, F., Gulick, J., Klevitsky, R., Hewett, T. E., Osinska, H. E., Lorenz, J. N., Brosseau, C., Federico, A. Alpert, N. R., Warshaw, D. M., Perryman, M. B., Helmke, S. M., Robbins, J. (2003) Analysis of myosin heavy chain functionality in the heart. J. Biol Chem. 278:17466-17474
Ishibashi, Y., Takahashi, M., Isomatsu, Y., Qiao, F., Iijima, Y., Shiraishi, H., Simsic, J. M., Baicu, C. F., Robbins, J., Zile, M. R., Cooper, G. (2003) Role of Microtubules versus Myosin Heavy Chain Isoforms in the Contractile Dysfunction of Hypertrophied Murine Cardiocytes. Am J Physiol Heart Circ Physiol 285: H1270-H1285.
Dorn, G. W. II, Robbins, J., Sugden, P. H. (2003) Phenotyping hypertrophy: Eschew obfuscation. Circ. Res. 92:1171-1175.
Sanbe, A., Gulick, J., Hanks, M. C., Liang, Q., Osinska, H., Robbins, J. (2003) Reengineering inducible cardiac-specific transgenesis with an attenuated myosin heavy chain promoter. Circ. Res. 92:609-616.
Krenz, M., Sanbe, A., Bouyer-Dalloz, F., Gulick, J., Klevitsky, R., Hewett, T. E., Osinska, H. E., Lorenz, J. N., Brosseau, C., Federico, A. Alpert, N. R., Warshaw, D. M., Perryman, M. B., Helmke, S. M., Robbins, J. (2003) Analysis of myosin heavy chain functionality in the heart. J. Biol Chem. 278: 17466-17474
Alpert, N. R., Brosseau, C., Federico, A., Krenz, M., Robbins, J., Warshaw, D. M. (2002) Molecular mechanics of mouse cardiac myosin isoforms. Am. J. Physiol. 283: H1446-H1454.
Contact Dr. Robbins
Jeffrey Robbins
Molecular Cardiovascular Biology
ML 7020
Children's Hospital
3333 Burnet Ave
Cincinnati, OH 45229-3039
jeff.robbins@cchmc.org
