© 1998 American Heart Association, Inc.
Original Contributions |
Targeted Overexpression of the Sarcoplasmic Reticulum Ca2+-ATPase Increases Cardiac Contractility in Transgenic Mouse Hearts
From the Division of Cardiology (D.L.B., Y.J., T.R., E.L., A.B., B.H., R.W., M.P.) and Department of Pharmacology and Cell Biophysics (I.L.G., G.G.), University of Cincinnati College of Medicine, Cincinnati, Ohio, and Section of Molecular and Cellular Cardiology (K.H., E.M.), The John Hopkins University, Baltimore, Md.
Correspondence to Muthu Periasamy, Division of Cardiology, University of Cincinnati College of Medicine, 231 Bethesda Avenue, ML542, Cincinnati, OH 45267. E-mail muthu.periasamy{at}uc.edu
Abstract—Cardiac
hypertrophy and heart failure are known to be associated
with a reduction in Ca2+-ATPase pump levels of the
sarcoplasmic reticulum (SR). To determine whether, and to what extent,
alterations in Ca2+ pump numbers can affect contraction and
relaxation parameters of the heart, we have overexpressed
the cardiac SR Ca2+-ATPase specifically in the mouse heart
using the 
-myosin heavy chain promoter. Analysis of 2
independent transgenic lines demonstrated that sarco(endo)plasmic
reticulum Ca2+-ATPase isoform (SERCA2a) mRNA levels
were increased 3.88±0.4-fold and 7.90±0.2-fold over those of the
control mice. SERCA2a protein levels were increased by 1.31±0.05-fold
and 1.54±0.05-fold in these lines despite high levels of mRNA,
suggesting that complex regulatory mechanisms may determine the SERCA2a
pump levels. The maximum velocity of Ca2+ uptake
(Vmax) was increased by 37%, demonstrating that increased
pump levels result in increased SR Ca2+ uptake function.
However, the apparent affinity of the SR Ca2+-ATPase for
Ca2+ remains unchanged in transgenic hearts. To evaluate
the effects of overexpression of the SR Ca2+ pump on
cardiac contractility, we used the isolated perfused
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 time to half relaxation. Measurements of
intracellular free calcium concentration and contractile force in
trabeculae revealed a doubling of Ca2+
transient amplitude, with a concomitant boost in
contractility. The present study demonstrates that
increases in SERCA2a pump levels can directly enhance contractile
function of the heart by increasing SR Ca2+ transport.
Key Words: sarcoplasmic reticulum Ca2+-ATPase • transgenic mice • Ca2+ uptake • working heart model
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