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

Debra L. Baker, Katsuji Hashimoto, Ingrid L. Grupp, Yong Ji, Thomas Reed, Evgenij Loukianov, Gunter Grupp, Ajit Bhagwhat, Brian Hoit, Richard Walsh, Eduardo Marban, Muthu Periasamy

Research output: Contribution to journalArticle

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 α-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 (V(max)) 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.

Original languageEnglish (US)
Pages (from-to)1205-1214
Number of pages10
JournalCirculation Research
Volume83
Issue number12
StatePublished - Dec 14 1998

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Keywords

  • Ca uptake
  • Sarcoplasmic reticulum Ca-ATPase
  • Transgenic mice
  • Working heart model

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Baker, D. L., Hashimoto, K., Grupp, I. L., Ji, Y., Reed, T., Loukianov, E., Grupp, G., Bhagwhat, A., Hoit, B., Walsh, R., Marban, E., & Periasamy, M. (1998). Targeted overexpression of the sarcoplasmic reticulum Ca2+-ATPase increases cardiac contractility in transgenic mouse hearts. Circulation Research, 83(12), 1205-1214.