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Cardiovascular Research Advance Access first published online on September 19, 2007
This version [Corrected Proof] published online on October 17, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm019
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Sarcalumenin alleviates stress-induced cardiac dysfunction by improving Ca2+ handling of the sarcoplasmic reticulum

Miei Shimura1, Susumu Minamisawa2,3,*, Hiroshi Takeshima4, Qibin Jiao2, Yunzhe Bai2, Satoshi Umemura1 and Yoshihiro Ishikawa2,5,6

1 Department of Internal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
2 Department of Physiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
3 Department of Life Science and Medical Bio-Science, Waseda University, Tokyo, Japan
4 Department of Medical Chemistry, Kyoto University Graduate School of Pharmaceutical Science, Kyoto, Japan
5 Department of Cell Biology and Molecular Medicine, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA
6 Department of Medicine (Cardiology), New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA

* Corresponding author. Tel: +81 45 787 2575; fax: +81 45 788 1470. E-mail address: sminamis{at}yokohama-cu.ac.jp

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 role in the regulation of Ca2+ cycling remains unclear.

Methods and results: To investigate whether SAR plays an important role 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.

KEYWORDS Calcium cycling; Heart failure; Pressure overload; SERCA; Protein stability

Time for primary review: 20 days


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