Sarcalumenin alleviates stress-induced cardiac dysfunction by improving Ca2+ handling of the sarcoplasmic reticulum

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.