Cardiac Disease: Alzheimer's of the Heart?
Human heart failure is the leading cause of death in the developed world and represents a final common endpoint for several disease entities, including hypertension, coronary artery disease, and the cardiomyopathies. The lack of pathogenic commonality is underscored by the large number of mutations in different classes of cardiac proteins. The data not only shows a toxic commonality for various classes of human heart disease but establishes a mechanistic link for heart failure with the neurodegenerative diseases as well. The data show, first in a genetically engineered mouse, that a dilated cardiomyopathy is characterized by the presence of protein aggregates that are indistinguishable from aggresomes, which are found in a wide variety of human neurodegenerative diseases such as Alzheimer's and Parkinson's. We then go on to show that the aggresomes present in the diseased hearts contain an amyloid oligomer that may represent the primary toxic species in Alzheimer's and other neurodegenerative diseases. Finally, we connect the animal models to human disease by showing that these soluble amyloids are present in a wide variety of human dilated and hypertrophic cardiomyopathies and that they are associated with the contractile apparatus. The data establish a new way of thinking about the pathogenic processes that underlie cardiovascular disease and link them to some well-defined neurodegenerative processes.
Related Publications
Wolf, C. M., Arad, M., Ahmad, F., A., Bernstein, S. A., Toka, O., Morley,G., Robbins, J., Seidman, J. G., Seidman, C. E., Berul, C. I. (2008) Reversibility of PRKAG2 glycogen storage cardiomyopathy and electrophysiologic manifestations. Circulation 117: 144-154
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
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 RA, Melendez J, Hambleton M, Sargent MA, Lorts A, Brunskill EW, Dorn GW 2nd, Conway SJ, Aronow BJ, Robbins J, Molkentin JD. (2007) Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling. Circ Res 101: 313-321
Maloyan A, Gulick J, Glabe CG, Kayed R, Robbins J. (2007) Exercise reverses pre-amyloid oligomer and prolongs survival in αB-crystallin-based desmin related cardiomyopathy. Proc Natl Acad Sci, USA 104: 5995-6000
Hsieh PCH, Davis ME, MacGillivray C, Gannon J, Molkentin JD, Robbins J, Lee RT. (2007) Evidence that stem cells refresh adult mammalian cardiomyocytes following injury: A genetic fate-mapping study. Nature Med 13, 970-974
Nakayama H, Chen X, Baines CP, Klevitsky R, Zhang L, Zhang H, Jaleel N, Chua BHL, Hewett TE, Robbins J, Houser SR, Molkentin JD. (2007) Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. J Clin Invest 117, 2123-2132
Purcell NH, Wilkins BJ, York A, Robbins J, Molkentin J. (2007) Genetic inhibition of cardiac ERK 1/2 promotes stress-induced apoptosis but has no effect on hypertrophy in vivo. Proc Natl Acad Sci, USA 104, 14074-14079
Galvez AS, Diwan A, Odley AM, Hahn HS, Osinska H, Melendez JG, Robbins J, Lynch RA, Marreez Y, Dorn GW. (2007). Cardiomyocyte degeneration with calpain deficiency reveals a critical role in protein homeostasis. Circ Res 100, 1071-1078
Wang XJ, Robbins J. (2006) Heart failure and protein quality control. Circ Res 99:1315-1328
Sanbe A, Osinska H, Villa C, Gulick J, Klevitsky R, Glabe CG, Kayed R, Robbins J. (2005) Reversal of amyloid-induced heart disease in desmin-related cardiomyopathy. Proc Natl Acad Sci U S A 102:13592-7.
Maloyan A, Sanbe A, Osinska H, Westfall M, Robinson D, Imahashi K, Murphy E, Robbins J. (2005) Mitochondrial dysfunction and apoptosis underlie the pathogenic process in alpha-B-crystallin desmin-related cardiomyopathy. Circulation 112:3451-61.
den Engelsman J, Gerrits D, de Jong WW, Robbins J, Kato K, Boelens WC. (2005) Nuclear import of αB-crystallin is phosphorylation-dependent and hampered by hyperphosphorylation of the myopathy-related mutant R120G. J Biol Chem 280:37139-48.
Gard JJ, Yamada K, Green KG, Eloff BC, Rosenbaum DS, Wang X, Robbins J, Schuessler RB, Yamada KA, Saffitz JE. (2005) Remodeling of gap junctions and slow conduction in a mouse model of desmin-related cardiomyopathy. Cardiovasc Res 67:539-47.
Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, Molkentin JD. (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658-62.
Sanbe, A., Osinska, H., Saffitz, J. E., Glabe, C. E., Kayed, R., Maloyan, A., Robbins, J. (2004) Desmin-related cardiomyopathy in transgenic mice: a cardiac amyloidosis. Proc. Natl. Acad. Sci., USA. 101(27):10132-10136
Wang, X. J., Osinska, H., Gerdes, A. M., Robbins, J. (2002) Desmin filaments and cardiac disease: establishing causality. J. Card. Failure. 8:S287-S292
I. Wang, X.-J.,, Klevitsky, R., Huang, W., Glasford, J., Li, F., Robbins, J. (2003) α-B-crystallin modulates protein aggregation of abnormal desmin. Circ Res (In press)
Wang, X-J., Osinska, H., Klevitsky, Dorn, G. W. II, Nieman, M., Lorenz, J. N., Gerdes, A. M., Witt, S., Kimball, T., Gulick, J., Robbins, J. (2001) A mouse model of desmin-related cardiomyopathy. Circulation 103, 2402-2407
Contact Dr. Robbins
Jeffrey Robbins
Molecular Cardiovascular Biology
ML 7020
Children's Hospital
3333 Burnet Ave
Cincinnati, OH 45229-3039
jeff.robbins@cchmc.org
