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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 laboratory gathered and published data that 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.
We showed, 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 showed that the aggresomes present in the diseased hearts contain an amyloid oligomer, which may represent the primary toxic species in Alzheimer’s and other neurodegenerative diseases.
Finally, we connected 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 established a new way of thinking about the pathogenic processes that underlie cardiovascular disease and link them to some well-defined neurodegenerative processes. These amyloid oligomers appear in both adult and pediatric heart disease, pointing to the importance of correct protein folding for normal heart function.
We have extended this work in an attempt to find therapeutic interventions. One potential pathway involves the process of autophagy, which the cell uses to recycle its internal components. We have now prepared mice in which we can control this process in the whole animal and are attempting to define the role of this process in potentially clearing the cardiomyocyte of the toxic amyloid oligomer and associated protein aggregates.
Lynch JM, Maillet M, Vanhoutte D, Schloemer A, Blair NS, Lynch KA, Aronow B, Osinska O, Prywes R, Lorenz JN, Lawler J, Robbins J. A thrombospondin-dependent pathway for a protective ER stress response. Cell 2012 149(6):1257-68.
Sciarretta, S, Zhai, P, Shao, D, Maejima, Y, Robbins, J, Volpe, M, Condorelli G, Sadoshima J. Rheb is a critical regulator of autophagy during myocardial ischemia: pathophysiological implications in obesity and metabolic syndrome. Circulation 2012 125:(9) 1134-1146.
Liao X, Sluimer JC, Wang Y, Subramanian M, Brown K, Pattison JS, Robbins J, Martinez J, Tabas I. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell (Metabolism) 2011. 15:545-52.
Tranter M, Liu Y, He S, Gulick J, Robbins J, Jones WK. Poly(glycoamidoamine)-mediated delivery of NF-κB oligodeoxynucleotide decoys affords therapeutic infarct size reduction in vivo. Mol. Therapy 2011. 20(3):601-8.
McLendon PM, Robbins J. Desmin-related cardiomyopathy: an unfolding story. Am J Physiol Heart Circ Physiol. 2011 Oct;301(4):H1220-8.
Pattison JS, Osinska H, Robbins J. Atg7 induces basal autophagy and rescues autophagic deficiency in CryABR120G cardiomyocytes. Circ Res. 2011 Jul 8;109(2):151-60.
Pattison JS, Robbins J. Autophagy and proteotoxicity in cardiomyocytes.Autophagy. 2011 Oct;7(10):1259-60.
Heineke J, Wollert KC, Osinska H, Sargent MA, York AJ, Robbins J, Molkentin JD. Calcineurin protects the heart in a murine model of dilated cardiomyopathy. J Mol Cell Cardiol. 2010 Jun;48(6):1080-7.
Maloyan A, Sayegh J, Osinska H, Chua BHL, Robbins J. Manipulation of death pathways in desmin-related cardiomyopathy. Circ. Res. May, 2010.
Maloyan A, Robbins J. Autophagy in Desmin-Related Cardiomyopathy: Thoughts at the Halfway Point. Autophagy. Jul, 2010.
Terrell D, Robbins J. Protein conformation-based disease: getting to the heart of the matter. Annual Review Physiol. 72: 1-3. 2010.
Maloyan A, Osinska H, Lammerding J, Lee RT, Cingolani OH, Kass D, Lorenz JN, Robbins J. Biochemical and mechanical dysfunction in a mouse model of desmin-related myopathy. Circ. Res. 104: 1021-1028. 2009.
Nicolaou P, Rodriguez P, Zhou X, Ren X, Qian J, Sadayappan S, Mitton B, Pathak A, Robbins J, Hajjar R, Jones K, Kranias EG. Inducible expression of active protein phosphatase-1 inhibitor-1 enhances basal cardiac function and protects against ischemic injury. Circ Res. 104: 1012-1020. 2009.
Gulick J, Robbins J. Cell-type-specific transgenesis in the mouse. Methods in Molecular Biology. 561: 91-106. 2009.
Krenz M, Gulick J, Osinska HE, Colbert MC, Molkentin JD, Robbins J. Role of ERK1/2 signaling in congenital valve malformations in Noonan syndrome. Proc Natl Acad Sci, USA. 105: 18930-18936. 2008.
Pattison JS, Robbins J. Protein misfolding and cardiac disease: Establishing cause and effect. Autophagy. 4(6). Aug, 2008.
Molkentin J, Robbins J. With great power comes great responsibility: using mouse genetics to study cardiac hypertrophy and failure. JMCC. 46: 130-136. 2008.
Moga MA, Nakamura T, Robbins J. Genetic approaches for changing the heart and dissecting complex syndromes. JMCC. 45: 148-155. 2008.
Pattison JS, Sanbe A, Maloyan A, Martin L, Osinska H, Klevitsky R, Robbins J. Cardiomyocyte expression of a polyglutamine preamyloid oligomer causes heart failure. Circulation. 117: 2743-2751. 2008.
Pattison JS, Waggoner JR, James J, Martin L, Gulick J, Osinska H, Klevitsky R, Kranias EG, Robbins J. Phospholamban overexpression in transgenic rabbits. Transgenic Res. 17: 157-170. 2008.
Millay DP, Sargent MA, Osinska H, Barton ER, Vuagniaux G, Sweeney HL, Robbins J, Molkentin JD. Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy. Nature Med. 14: 442-447. 2008.
Pinz I, Robbins J, Benjamin IJ, Ingwall J. 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. 2008.
Heineke J, Auger-Messier M, Xu J, Oka T, Sargent MA, York A, Klevitsky R, Vaikunth S, Duncan SA, Aronow BJ, Robbins J, Crombleholm TM, Molkentin JD. Cardiomyocyte GATA4 functions as a stress-responsive regulator of angiogenesis in the murine heart. J. Clin. Invest. 117: 3198-3210. 2007.
Diwan A, Krenz M, Sayed FM, Wanasapura J, Ren X, Matkovich SJ, Koesters AG, Li H, Kirshenbaum LA, Robbins J, Jones WK, Dorn GW 2nd. Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of bnip3 restrains postinfarction remodeling in mice. J. Clin. Invest. 117: 2825-2833. 2007.
Maloyan A, Gulick J, Glabe CG, Kayed R, Robbins J. Exercise reverses preamyloid oligomer and prolongs survival in alphaB-crystallin-based desmin-related cardiomyopathy. Proc. Natl. Acad. Sci. U S A. 104: 5995-6000. 2007.
Nakayama H, Chen X, Baines CP, Klevitsky R, Zhang L, Zhang H, Jaleel N, Chua BHL, Hewett TE, Robbins J, Houser SR, Molkentin JD. Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. J Clin. Invest. 117, 2123-2132. 2007.
Purcell NH, Wilkins BJ, York A, Robbins J, Molkentin J. Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo.Proc. Natl. Acad. Sci. USA. 104, 14074-14079. 2007.
Galvez AS,Diwan A, Odley AM, Hahn HS, Osinska H, Melendez JG, Robbins J,Lynch RA, Marreez Y, Dorn GW. Cardiomyocyte degeneration with calpain deficiency reveals a critical role in protein homeostasis. Circ. Res. 100, 1071-1078. 2007.
Yutzey KE, Robbins J. Principles of genetic murine models for cardiac disease. Circulation 115: 792-799. 2007.
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