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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.
McLendon PM, Robbins J. Proteotoxicity and Cardiac Dysfunction. Circ Res. 2015 May 22;116(11):1863-1882.
Bhandary B, Robbins J. Giving credence to controls: Avoiding the false phenotype. J Mol Cell Cardiol. 2015 Jul 31;86:136-137.
Ratner N, Nakafuku M, Waclaw RR. The protein tyrosine phosphatase shp2 is required for the generation of oligodendrocyte progenitor cells and myelination in the mouse telencephalon. J Neurosci. 2014 Mar 5;34(10):3767-78
Sandri M, Robbins J. Proteotoxicity: An underappreciated pathology in cardiac disease. J Mol Cell Cardiol. 2014 Jun;71c:3-10
Wang X, Robbins J. Proteasomal and lysosomal protein degradation and heart disease. J Mol Cell Cardiol. 2014 Jun;71c:16-24
Gupta MK, Gulick J, Liu R, Wang X, Molkentin JD, Robbins J.Required for Efficient Protein Quality Control in Cardiomyocytes. Circ Res. 2014;115:721-729.
McLendon PM, Ferguson BS, Osinska H, Bhuiyan MS, James J, McKinsey TA, Robbins J. Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy. Proc Natl Acad Sci U S A. 2014 Dec 2;111(48):E5178-86.
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. 2010;72:1-3.
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. 2009;104: 1021-1028.
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. 2009;104: 1012-1020.
Gulick J, Robbins J. Cell-type-specific transgenesis in the mouse. Methods in Molecular Biology. 2009;561: 91-106.
Molkentin J, Robbins J. With great power comes great responsibility: using mouse genetics to study cardiac hypertrophy and failure. JMCC. 2009 Feb;46(2):130-6.
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. 2008;105:18930-18936.
Pattison JS, Robbins J. Protein misfolding and cardiac disease: Establishing cause and effect. Autophagy. 2008 Aug;4(6):821-3.
Moga MA, Nakamura T, Robbins J. Genetic approaches for changing the heart and dissecting complex syndromes. JMCC. 2008;45: 148-155.
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. 2008;117:2743-2751.
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. 2008;17:157-170.
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. 2008;14:442-447.
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. 2008;22:84-92.
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. 2007;117:3198-3210.
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. 2007;117:2825-2833.
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. 2007;104:5995-6000.
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. 2007;117, 2123-2132.
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. 2007;104, 14074-14079.
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. 2007;100, 1071-1078.
Yutzey KE, Robbins J. Principles of genetic murine models for cardiac disease. Circulation. 2007;115:792-799.
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