Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 19, 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
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 and Medicine (Cardiology), New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, United States
Address correspondence to Susumu Minamisawa, Department of Physiology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan, Phone: +81-(0)45-787-2575, Fax: +81-(0)45-788-1470, e-mail: 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: 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.
Results: We found that SAR expression was significantly downregulated in hypertrophic hearts from three independent animal models. SAR-KO mice experienced higher mortality than wild-type mice did after TAC. TAC significantly downregulated SERCA2a protein but not mRNA in the SAR-KO hearts, whereas it minimally did so in hearts from wild-type mice. Accordingly, SR Ca2+ uptake and cardiac function were significantly reduced in SAR-KO mice after TAC. Then we found that SAR was coimmunoprecipitated with SERCA2a in cDNA-transfected HEK293T cells and mouse ventricular muscles, and that SERCA2a-mediated Ca2+ uptake was augmented when SAR was coexpressed in HEK293T cells. Furthermore, SAR significantly prolonged the half-life of SERCA2a protein in HEK293T cells.
Conclusions: 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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