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1 Medicine, University of California, San Diego, La Jolla, California, USA
2 Internal Medicine, University of Utah, School of Medicine, Salt Lake City, Utah, USA; George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah, USA
* To whom correspondence should be addressed. E-mail: wdillmann{at}ucsd.edu.
Delayed cardiac relaxation in failing hearts has been attributed to reduced activity and/or expression of SERCA2a. While constitutive over-expression of SERCA2a has proven effective in preventing cardiac dysfunction, it is unclear if increasing SERCA2a expression in hearts with pre-existing hypertrophy will be therapeutic. To test this hypothesis, we generated a binary transgenic system (BTG) that allows tetracycline-inducible, cardiac-specific SERCA2a expression. In this system (tet-on SERCA2a), a FLAG-tagged SERCA2a transgene is expressed in the presence of doxycycline (DOX) but not in the absence of DOX (2.3 fold more mRNA, 45% more SERCA2a protein). Calcium transients measured in isolated cardiac myocytes from non-banded DOX treated BTG mice showed an accelerated calcium decline and an increased systolic Ca2+ peak. Sarcoplasmic reticulum (SR) calcium loading was increased by 45% in BTG mice. In the presence of pressure overload (aortic banding), echocardiographic analysis revealed that expression of SERCA2a-FLAG caused an improvement in fractional shortening (%FS). SERCA2a-FLAG expression alleviated the resultant cardiac dysfunction. This was illustrated by an increase in the rate of decline of the calcium transient. Cell shortening and SR calcium loading were also improved in cardiac myocytes isolated from banded BTG mice after SERCA2a over-expression. In conclusion, we have generated a novel transgenic mouse that conditionally over-expresses SERCA2a. This model is suitable for both long and short term studies of the effects of controlled SERCA2a expression on cardiac function. In addition, inducible over-expression of SERCA2a improved cardiac function and calcium handling in mice with established contractile dysfunction.
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