© 1998 American Heart Association, Inc.
Original Contributions |
Enhanced Myocardial Contractility and Increased Ca2+ Transport Function in Transgenic Hearts Expressing the Fast-Twitch Skeletal Muscle Sarcoplasmic Reticulum Ca2+-ATPase
From the Division of Cardiology (E.L., Y.J., D.L.K., D.L.B., T.L., R.A.W., M.P.), Departments of Pharmacology and Cell Biophysics (I.L.G.) and Molecular and Cellular Physiology (G.G.), University of Cincinnati College of Medicine, Cincinnati, Ohio, and Department of Medical Biochemistry, University of Calgary (J.L.), Alberta, Canada.
Correspondence to Muthu Periasamy, PhD, Director of Molecular Cardiology, University of Cincinnati College of Medicine, 231 Bethesda Ave, ML0542, Cincinnati, OH 45267-0542. E-mail muthu.periasamy{at}uc.edu
Abstract—In this study, we
investigated whether the fast-twitch skeletal muscle sarco(endo)plasmic
reticulum Ca2+ transport pump (SERCA1a) can functionally
substitute the cardiac SERCA2a isoform and how its overexpression
affects cardiac contractility. For this purpose, we
generated transgenic (TG) mice that specifically overexpress SERCA1a in
the heart, using the cardiac-specific 
-myosin heavy chain promoter.
Ectopic expression of SERCA1a resulted in a 2.5-fold increase in the
amount of total SERCA protein. At the same time, the level of the
endogenous SERCA2a protein was decreased by 50%, whereas
the level of other muscle proteins, including calsequestrin,
phospholamban, actin, and tropomyosin, remained unchanged. The
steady-state level of SERCA phosphoenzyme intermediate was increased
2.5-fold, and the maximal velocity of Ca2+ uptake was
increased 1.7-fold in TG hearts, demonstrating that the overexpressed
protein is functional. Although the basal cytosolic calcium signal was
decreased by 38% in TG cardiomyocytes, the amplitude of
cytosolic calcium signal was increased by 71.8%. The rate of calcium
resequestration was also increased in TG myocytes, which was reflected
by a 51.6% decrease in the normalized time to 80% decay of calcium
signal. This resulted in considerably increased peak rates of myocyte
shortening and relengthening (50.0% and 66.6%, respectively). Cardiac
functional analysis using isolated work-performing heart
preparations revealed significantly faster rates of contraction and
relaxation in TG hearts (41.9% and 39.5%, respectively). The time to
peak pressure and the time to half-relaxation were shorter (29.1% and
32.7%, respectively). In conclusion, our study demonstrates that the
SERCA1a pump can functionally substitute endogenous
SERCA2a, and its overexpression significantly enhances Ca2+
transport and contractile function of the myocardium. These
results also demonstrate that the SERCA pump level is a critical
determinant of cardiac contractility.
Key Words: SERCA1a • overexpression • transgenic mouse • cardiac contractility
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|
|
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|
|
|
|
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|
|
|
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|
|
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|
|
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|
|
|
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|
|
|
|
|
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|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
G. Hasenfuss Calcium Pump Overexpression and Myocardial Function : Implications for Gene Therapy of Myocardial Failure Circ. Res., November 2, 1998; 83(9): 966 - 968. [Full Text] [PDF]
|
|
|
|
|
|
A. L. Greene, M. J. Lalli, Y. Ji, G. J. Babu, I. Grupp, M. Sussman, and M. Periasamy Overexpression of SERCA2b in the Heart Leads to an Increase in Sarcoplasmic Reticulum Calcium Transport Function and Increased Cardiac Contractility J. Biol. Chem., August 4, 2000; 275(32): 24722 - 24727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ji, M. J. Lalli, G. J. Babu, Y. Xu, D. L. Kirkpatrick, L. H. Liu, N. Chiamvimonvat, R. A. Walsh, G. E. Shull, and M. Periasamy Disruption of a Single Copy of the SERCA2 Gene Results in Altered Ca2+ Homeostasis and Cardiomyocyte Function J. Biol. Chem., November 22, 2000; 275(48): 38073 - 38080. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Jane Lalli, J. Yong, V. Prasad, K. Hashimoto, D. Plank, G. J. Babu, D. Kirkpatrick, R. A. Walsh, M. Sussman, A. Yatani, et al. Sarcoplasmic Reticulum Ca2+ ATPase (SERCA) 1a Structurally Substitutes for SERCA2a in the Cardiac Sarcoplasmic Reticulum and Increases Cardiac Ca2+ Handling Capacity Circ. Res., July 20, 2001; 89(2): 160 - 167. [Abstract] [Full Text] [PDF]
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