Sarcalumenin plays a critical role in age-related cardiac dysfunction due to decreases in SERCA2a expression and activity
Sarcalumenin plays a critical role in age-related cardiac dysfunction due to decreases in SERCA2a expression and activity
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DOI：
10.1016/j.ceca.2011.10.003
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发表时间：
2012-01-01
期刊：
影响因子：
4
通讯作者：
Minamisawa, Susumu
中科院分区：
文献类型：
--
作者：
Jiao, Qibin;Takeshima, Hiroshi;Minamisawa, Susumu
受损的Ca2+再摄取到肌浆网（SR）是心脏老化中心力衰竭的主要发病机制。Sarcalumenin （SAR）是一种位于纵向SR的Ca2+结合糖蛋白，通过与SR Ca2+- atp酶（SERCA）相互作用调节Ca2+再摄取。我们发现，在衰老野生型小鼠（18个月大）中，SAR和SERCA2蛋白的表达水平均显著下调，并且SAR蛋白的下调先于SERCA2蛋白的下调。SERCA2蛋白的下调在衰老的SARKO小鼠中比在年龄匹配的衰老野生型小鼠中更大，这至少部分是由于SARKO小鼠中SERCA2蛋白的进行性降解。衰老的SARKO小鼠表现出典型的心力衰竭症状，如交感神经活动增加、运动耐受性受损和心脏应激生物标志物上调。因此，老年SARKO患者的心功能逐渐下降。我们还发现，衰老SARKO小鼠内质网（ER）应激相关基因如x-box结合蛋白1 （XBP1）的表达水平显著升高，表明衰老SARKO小鼠出现内质网应激。因此，我们揭示了SAR在维持老年人群SERCA2a Ca2+转运活性和心功能中的重要作用。(C) 2011 Elsevier Ltd.版权所有。
Impaired Ca2+ reuptake into the sarcoplasmic reticulum (SR) underlies a primary pathogenesis of heart failure in the aging heart. Sarcalumenin (SAR), a Ca2+-binding glycoprotein located in the longitudinal SR, regulates Ca2+ reuptake by interacting with SR Ca2+-ATPase (SERCA). Here we found that the expression levels of both SAR and SERCA2 proteins were significantly downregulated in senescent wild-type mice (18-month old) and that downregulation of SAR protein preceded downregulation of SERCA2 protein. The downregulation of SERCA2 protein was greater in senescent SARKO mice than in age-matched senescent wild-type mice, which was at least in part due to progressive degradation of SERCA2 protein in SARKO mice. Senescent SARKO mice exhibited typical findings of heart failure such as increased sympathetic activity, impaired exercise tolerance, and upregulation of biomarkers of cardiac stress. Consequently, cardiac function was progressively decreased in senescent SARKO. We also found that the expression levels of endoplasmic reticulum (ER) stress-related genes such as x-box binding protein 1 (XBP1) were significantly increased in senescent SARKO mice, indicating that senescent SARKO mice exhibited ER stress. Thus we uncovered the important role of SAR in maintaining Ca2+ transport activity of SERCA2a and cardiac function in the senescent population. (C) 2011 Elsevier Ltd. All rights reserved.