Sarcalumenin alleviates stress-induced cardiac dysfunction by improving Ca2+ handling of the sarcoplasmic reticulum
Sarcalumenin alleviates stress-induced cardiac dysfunction by improving Ca2+ handling of the sarcoplasmic reticulum
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DOI：
10.1093/cvr/cvm019
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发表时间：
2008-01-15
影响因子：
10.8
通讯作者：
Ishikawa, Yoshihiro
中科院分区：
文献类型：
--
作者：
Shimura, Miei;Minamisawa, Susumu;Ishikawa, Yoshihiro
Sarcalumenin（SAR）是一种钙离子结合蛋白，表达于横纹肌细胞的纵行肌浆网（SR）。虽然它的Ca 2+结合特性是类似的钙螯合蛋白，其ROTE在调节Ca 2 + cycling仍然不清楚。方法和结果要调查SAR是否起着重要的ROTE在维持心脏功能的压力过载stress，SAR基因敲除（SAR-KO）小鼠进行横向主动脉缩窄（TAC）。为了研究SAR与SR Ca ~（2+）通道、SERCA_（2a）的心脏类型的关系，我们设计了使用培养细胞表达的cDNA。我们发现，SAR的表达显着下调肥厚的心脏从三个独立的动物模型。SAR-KO小鼠在TAC后的死亡率高于野生型（WT）小鼠。TAC在SAR-KO心脏中显著下调SERCA 2a蛋白，但不下调mRNA，而在WT小鼠的心脏中下调幅度最小。因此，TAC后SAR-KO小鼠SR Ca 2+摄取和心脏功能显著降低。然后我们发现SAR与SERCA 2a在cDNA转染的HEK 293 T细胞和小鼠心室肌中共免疫沉淀，并且当SAR在HEK 293 T细胞中共表达时，SERCA 2a介导的Ca 2+摄取增加。结论SAR与SERCA 2a的功能性相互作用增强了SERCA 2a蛋白的稳定性，促进了Ca ~（2+）在SR中的螯合，从而在压力负荷等生物力学应激条件下保护心脏功能中发挥重要作用。
Aims Sarcalumenin (SAR) is a Ca2+-binding protein expressed in the longitudinal sarcoplasmic reticulum (SR) of striated muscle cells. Although its Ca2+-binding property is similar to that of calsequestrin, its rote in the regulation of Ca2+ cycling remains unclear.Methods and results To investigate whether SAR plays an important rote in maintaining cardiac function under pressure overload stress, SAR-knockout (SAR-KO) mice were subjected to transverse aortic constriction (TAC). To examine the relation of SAR with cardiac type of SR Ca2+ PUMP, SERCA2a, we designed cDNA expression using cultured cells. We found that SAR expression was significantly downregulated in hypertrophic hearts from three independent animal, models. SAR-KO mice experienced higher mortality than did wild-type (WT) mice after TAC. TAC significantly downregulated SERCA2a protein but not mRNA in the SAR-KO hearts, whereas it minimally did so in hearts from WT mice. Accordingly, SR Ca2+ uptake and cardiac function were significantly reduced in SAR-KO mice after TAC. Then we found that SAR was co-immunoprecipitated with SERCA2a, in cDNA-transfected HEK293T cells and mouse ventricular muscles, and that SERCA2a-mediated Ca2+ uptake was augmented when SAR was co-expressed in HEK293T cells. Furthermore, SAR significantly prolonged the half-life of SERCA2a protein in HEK293T cells.Conclusion These findings suggest that functional interaction between SAR and SERCA2a enhances protein stability of SERCA2a and facilitates Ca2+ sequestration into the SR. Thus the SAR-SERCA2a interaction plays an essential role in preserving cardiac function under biomechanical stresses such as pressure overload.