Sarcalumenin plays a critical role in age-related cardiac dysfunction due to decreases in SERCA2a expression and activity

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• 作者：Qibin Jiao^a ; Hiroshi Takeshima^b ; Yoshihiro Ishikawa^c ; Susumu Minamisawa^a ; ^c ; ^{sminamis@waseda.jp}
• 关键词：Sarcoplasmic reticulum ; SERCA2 ; ER stress ; Diastolic function ; Heart failure ; Heart rate variability
• 刊名：Cell Calcium
• 出版年：2012
• 出版时间：January 2012
• 年：2012
• 卷：51
• 期：1
• 页码：31-39
• 全文大小：874 K

文摘

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.