Targeted overexpression of the sarcoplasmic reticulum Ca2+-ATPase increases cardiac contractility in transgenic mouse hearts

Cardiac hypertrophy and heart failure are known to be associated with a red uction in Ca2+-ATPase pump levels of the sarcoplasmic reticulum (SR). To de termine whether, and to what extent, alterations in Ca2+ pump numbers can a ffect contraction and relaxation parameters of the heart, we have overexpre ssed the cardiac SR Ca2+-ATPase specifically in the mouse heart using the a lpha-myosin heavy chain promoter. Analysis of 2 independent transgenic line s demonstrated that sarco(endo)plasmic reticulum Ca2+-ATPase isoform (SERCA 2a) mRNA levels were increased 3.88+/-0.4-fold and 7.90+/-0.2-fold over tho se of the control mice. SERCA2a protein levels were increased by 1.31+/-0.0 5-fold and 1.54+/-0.05-fold in these lines despite high levels of mRNA, sug gesting that complex regulatory mechanisms may determine the SERCA2a pump l evels. The maximum velocity of Ca2+ uptake (V-max) was increased by 37%, de monstrating that increased pump levels result in increased SR Ca2+ uptake f unction. However, the apparent affinity of the SR Ca2+-ATPase for Ca2+ rema ins unchanged in transgenic hearts. To evaluate the effects of overexpressi on of the SR Ca2+ pump on cardiac contractility, we used the isolated perfu sed work-performing heart model. The transgenic hearts showed significantly higher myocardial contractile function, as indicated by increased maximal rates of pressure development for contraction (+dP/dt) and relaxation (-dP/ dt), together with shortening of the normalized time to peak pressure and t ime to half relaxation. Measurements of intracellular free calcium concentr ation and contractile force in trabeculae revealed a doubling of Ca2+ trans ient amplitude, with a concomitant boost in contractility. The present stud y demonstrates that increases in SERCA2a pump levels can directly enhance c ontractile function of the heart by increasing SR Ca2+ transport.