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Research

Comparative Proteomics Profiling of a Phospholamban Mutant Mouse Model of Dilated Cardiomyopathy Reveals Progressive Intracellular Stress Responses^*,S

From the ^a Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G 1L6, Canada, ^b Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario M5S 3E2, Canada, ^c Department of Physiology, University of Toronto, Toronto, Ontario M5G 1A8, Canada, ^g Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland, ^j Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts 02115, ^h Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario M5S 3G4, Canada, and ⁱ Roche Diagnostics, 82377 Penzburg, Germany

Defective mobilization of Ca²⁺ by cardiomyocytes can lead to cardiac insufficiency, but the causative mechanisms leading to congestive heart failure (HF) remain unclear. In the present study we performed exhaustive global proteomics surveys of cardiac ventricle isolated from a mouse model of cardiomyopathy overexpressing a phospholamban mutant, R9C (PLN-R9C), and exhibiting impaired Ca²⁺ handling and death at 24 weeks and compared them with normal control littermates. The relative expression patterns of 6190 high confidence proteins were monitored by shotgun tandem mass spectrometry at 8, 16, and 24 weeks of disease progression. Significant differential abundance of 593 proteins was detected. These proteins mapped to select biological pathways such as endoplasmic reticulum stress response, cytoskeletal remodeling, and apoptosis and included known biomarkers of HF (e.g. brain natriuretic peptide/atrial natriuretic factor and angiotensin-converting enzyme) and other indicators of presymptomatic functional impairment. These altered proteomic profiles were concordant with cognate mRNA patterns recorded in parallel using high density mRNA microarrays, and top candidates were validated by RT-PCR and Western blotting. Mapping of our highest ranked proteins against a human diseased explant and to available data sets indicated that many of these proteins could serve as markers of disease. Indeed we showed that several of these proteins are detectable in mouse and human plasma and display differential abundance in the plasma of diseased mice and affected patients. These results offer a systems-wide perspective of the dynamic maladaptions associated with impaired Ca²⁺ homeostasis that perturb myocyte function and ultimately converge to cause HF.

^l The Ontario Research Chair in Biomarkers. To whom correspondence may be addressed: Donnelly Centre for Cellular and Biomedical Research, University of Toronto, 160 College St., Toronto, Ontario M5S 3E1, Canada. Tel.: 416-946-7281; Fax: 416-978-7437; E-mail: andrew.emili{at}utoronto.ca