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Proteomic analysis was carried out by subjecting fractionated cardiac samples from CNA mice and their WT littermates to gel-free liquid chromatography linked to shotgun tandem mass spectrometry. We identified 1,918 proteins with high confidence, of which 290 were differentially expressed. Microarray analysis of the same tissue provided us with alterations in the ventricular transcriptome. Because bioinformatic analyses of both the proteome and transcriptome demonstrated the up-regulation of endoplasmic reticulum stress, we validated its occurrence in adult CNA hearts through a series of immunoblots and RT-PCR analyses. Endoplasmic reticulum stress often leads to increased apoptosis, but apoptosis was minimal in CNA hearts, suggesting that activated calcineurin might protect against apoptosis. Indeed, the viability of cultured neonatal mouse cardiomyocytes (NCMs) from CNA mice was higher than WT after serum starvation, an apoptotic trigger. Proteomic data identified \u03b1-crystallin B (Cryab) as a potential mediator of this protective effect and we showed that silencing of Cryab via lentivector-mediated transduction of shRNAs in NCMs led to a significant reduction in NCM viability and loss of protection against apoptosis. The identification of Cryab as a downstream effector of calcineurin-induced protection against apoptosis will permit elucidation of its role in cardiac apoptosis and its potential as a therapeutic target.<\/jats:p>","DOI":"10.1073\/pnas.1013555107","type":"journal-article","created":{"date-parts":[[2010,10,11]],"date-time":"2010-10-11T20:53:33Z","timestamp":1286830413000},"page":"18481-18486","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":55,"title":["Constitutively active calcineurin induces cardiac endoplasmic reticulum stress and protects against apoptosis that is mediated by \u03b1-crystallin-B"],"prefix":"10.1073","volume":"107","author":[{"given":"Nicolas","family":"Bousette","sequence":"first","affiliation":[{"name":"Department of Physiology, University of Toronto, Toronto, ON, Canada M5G 1A8;"},{"name":"Heart and Stroke\/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada M5S 3E2;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaan","family":"Chugh","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Toronto, Toronto, ON, Canada M5G 1A8;"},{"name":"Heart and Stroke\/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada M5S 3E2;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Fong","sequence":"additional","affiliation":[{"name":"The Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, Canada M5G 1L6;"},{"name":"The Charles H. 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