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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Constitutively active calcineurin induces cardiac endoplasmic reticulum stress and protects against apoptosis that is mediated by α-crystallin-B
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Constitutively active calcineurin induces cardiac endoplasmic reticulum stress and protects against apoptosis that is mediated by α-crystallin-B

机译：组成型活性钙调神经磷酸酶诱导心脏内质网应激，并保护由α-晶状体蛋白B介导的细胞凋亡

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摘要

Cardiac-specific overexpression of a constitutively active form of calcineurin A (CNA) leads directly to cardiac hypertrophy in the CNA mouse model. Because cardiac hypertrophy is a prominent characteristic of many cardiomyopathies, we deduced that delineating the proteomic profile of ventricular tissue from this model might identify novel, widely applicable therapeutic targets. Proteomic analysis was carried out by subjecting fractionated cardiac samples from CNA mice and their WT littermates to gel-free liquid chroma-tography 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 cardio-myocytes (NCMs) from CNA mice was higher than WT after serum starvation, an apoptotic trigger. Proteomic data identified a-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.
机译：钙调神经磷酸酶A（CNA）的组成型活性形式的心脏特异性过度表达直接导致CNA小鼠模型的心脏肥大。由于心脏肥大是许多心肌病的突出特征，因此我们推断，从该模型描述心室组织的蛋白质组学特征可能会确定新的，广泛适用的治疗靶标。蛋白质组学分析是通过对来自CNA小鼠及其WT同窝幼仔的分级心脏样品进行与shot弹枪串联质谱联用的无凝胶液相色谱法进行的。我们以高可信度鉴定了1,918个蛋白质，其中290个被差异表达。相同组织的微阵列分析为我们提供了心室转录组的改变。由于蛋白质组和转录组的生物信息学分析表明内质网应激的上调，我们通过一系列免疫印迹和RT-PCR分析验证了其在成年CNA心脏中的发生。内质网应激通常会导致细胞凋亡增加，但CNA心脏中的细胞凋亡极少，这表明活化的钙调神经磷酸酶可能可以防止细胞凋亡。确实，来自CNA小鼠的培养的新生鼠心肌细胞（NCM）的活力在血清饥饿（凋亡的触发因素）之后高于WT。蛋白质组学数据确定α-晶状体蛋白B（Cryab）是这种保护作用的潜在介体，并且我们显示通过慢载体介导的shRNA在NCM中的转导而使Cryab沉默导致NCM活力显着降低和对凋亡的保护作用丧失。将Cryab鉴定为钙调神经磷酸酶诱导的抗凋亡保护作用的下游效应物，将阐明其在心脏细胞凋亡中的作用及其作为治疗靶标的潜力。

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    Nicolas Bousette; Shaan Chugh; Vincent Fong; Ruth lsserlin; Kyoung-Han Kim; Allen Volchuk; Peter H. Backx; Peter Liu; Thomas Kislinger; David H. MacLennan; Andrew Emili; Anthony O. Gramolini;

  • 作者单位

    Department of Physiology, University of Toronto, Toronto, ON, Canada M5G 1A8 Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada M5S 3E2;

    rnDepartment of Physiology, University of Toronto, Toronto, ON, Canada M5G 1A8 Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada M5S 3E2;

    rnThe Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, Canada M5G 1L6 The Charles H. Best Institute and Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada M5S 3E1;

    rnThe Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, Canada M5G 1L6 The Charles H. Best Institute and Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada M5S 3E1;

    rnDepartment of Physiology, University of Toronto, Toronto, ON, Canada M5G 1A8;

    rnDivision of Cellular and Molecular Biology, Toronto General Research Institute University Health Network, Toronto, ON, Canada M5G 1L7;

    rnDepartment of Physiology, University of Toronto, Toronto, ON, Canada M5G 1A8 Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada M5S 3E2;

    rnDepartment of Medicine, University Health Network, Toronto, ON, Canada M5G 2C4;

    rnDepartment of Medical Biophysics, University Health Network, Toronto, ON, Canada M5G 1L7;

    rnThe Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, Canada M5G 1L6 The Charles H. Best Institute and Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada M5S 3E1;

    rnThe Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, Canada M5G 1L6 The Charles H. Best Institute and Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada M5S 3E1;

    rnDepartment of Physiology, University of Toronto, Toronto, ON, Canada M5G 1A8 Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada M5S 3E2;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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