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P16
Heart function in adult cardiac Serca2null mice.
Kristin Brevik Andersson1,2, Jon Arne Kro Birkeland1,2, Alexandra Vanessa Finsen1,2, William E.
Louch1,2, Ivar Sjaastad1,2,3, Yibin Wang4, Ju Chen5, Jeffery D. Molkentin6, Kenneth R. Chien7, Ole M.
Sejersted1,2, Geir Christensen1,2
1
Institute for Experimental Medical Research, Ullevaal University Hospital
Center for Heart Failure Research, University of Oslo
3 Department of Cardiology, Heart and Lung Center, Ullevaal University Hospital
4 Departments of Anesthesiology, Physiology and Medicine, David Geffen School of Medicine,
University of California Los Angeles, Los Angeles, CA, USA.
5 Institute of Molecular Medicine, University of California San Diego, La Jolla, California, USA.
6 Department of Pediatrics, University of Cincinnati, Children's Hospital Medical Center, Division of
Molecular Cardiovascular Biology, Cincinnati, Ohio, USA.
7 Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts,
USA.
2
The generation of Ca2+ transients in cardiomyocytes is essential for heart function. The SERCA2
pump maintains the sarcoplasmic reticulum (SR) Ca2+ store by sequestration of Ca2+ from cytosol into
the SR. Loss of SERCA2 in adult hearts is therefore expected to cause immediate severe myocardial
contractile dysfunction and death. We have generated a new mouse model to test this hypothesis.
Homozygous Serca2flox mice, were mated with Tg(MHC-MerCreMer) transgenic mice.
Cardiomyocyte-specific Serca2 deletion may be induced by injection of tamoxifen in adult mice.
Tamoxifen-injected Serca2flox/floxTg(MHC-MerCreMer) and control Serca2flox/flox mice are termed
SERCA2KO and SERCA2FF mice, respectively.
At 4 weeks after tamoxifen induction, the Serca2 gene was efficiently deleted in SERCA2KO
myocardium (<3% Serca2 mRNA and <5% SERCA2 protein). Functional thapsigargin-sensitive Ca2+
ATPase was reduced to 15 % of SERCA2FF controls, as measured by 32P-incorporation in tissue
homogenates. In isolated cardiomyocytes, we did not detect SERCA2, SERCA1 or SERCA3 proteins.
Strikingly, SERCA2KO mice did not present clinical signs of circulatory failure at this timepoint.
Contractile parameters were modestly affected, and cardiac output was 80 % of SERCA2 FF control
mice. The left atrium was slightly dilated. We found no evidence of hypertrophy, disarray, necrosis or
fibrosis in histological sections, nor induction of hypertrophy markers ANP or BNP. However, the lung
weight was slightly increased, suggesting some myocardial dysfunction. Protein expression of the LCa2+ channel alpha2 regulatory subunit, sodium/calcium exchanger NCX1 and plasma membrane
Ca2+-ATPase (PMCA) were all increased in SERCA2KO mice, suggesting alterations in Ca 2+ fluxes
over the plasma membrane. Cardiomyocyte function in 4 week SERCA2KO mice is presented in the
accompanying poster.
In conclusion, the SERCA2KO mouse represents a new and unique phenotype of Ca 2+-handling in
vivo. The model should be useful for mechanistic studies of Ca2+ transport, compensatory
mechanisms and progressive heart failure in vivo.