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Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation.

Publication ,  Journal Article
He, H; Giordano, FJ; Hilal-Dandan, R; Choi, DJ; Rockman, HA; McDonough, PM; Bluhm, WF; Meyer, M; Sayen, MR; Swanson, E; Dillmann, WH
Published in: J Clin Invest
July 15, 1997

The Ca2+ ATPase of the sarcoplasmic reticulum (SERCA2) plays a dominant role in lowering cytoplasmic calcium levels during cardiac relaxation and reduction of its activity has been linked to delayed diastolic relaxation in hypothyroid and failing hearts. To determine the contractile alterations resulting from increased SERCA2 expression, we generated transgenic mice overexpressing a rat SERCA2 transgene. Characterization of a heterozygous transgenic mouse line (CJ5) showed that the amount of SERCA2 mRNA and protein increased 2. 6-fold and 1.2-fold, respectively, relative to control mice. Determination of the relative synthesis rate of SERCA2 protein showed an 82% increase. The mRNA levels of some of the other genes involved in calcium handling, such as the ryanodine receptor and calsequestrin, remained unchanged, but the mRNA levels of phospholamban and Na+/Ca2+ exchanger increased 1.4-fold and 1.8-fold, respectively. The increase in phospholamban or Na+/Ca2+ exchanger mRNAs did not, however, result in changes in protein levels. Functional analysis of calcium handling and contractile parameters in isolated cardiac myocytes indicated that the intracellular calcium decline (t1/2) and myocyte relengthening (t1/2) were accelerated by 23 and 22%, respectively. In addition, the rate of myocyte shortening was also significantly faster. In isolated papillary muscle from SERCA2 transgenic mice, the time to half maximum postrest potentiation was significantly shorter than in negative littermates. Furthermore, cardiac function measured in vivo, demonstrated significantly accelerated contraction and relaxation in SERCA2 transgenic mice that were further augmented in both groups with isoproterenol administration. Similar results were obtained for the contractile performance of myocytes isolated from a separate line (CJ2) of homozygous SERCA2 transgenic mice. Our findings suggest, for the first time, that increased SERCA2 expression is feasible in vivo and results in enhanced calcium transients, myocardial contractility, and relaxation that may have further therapeutic implications.

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Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

July 15, 1997

Volume

100

Issue

2

Start / End Page

380 / 389

Location

United States

Related Subject Headings

  • Ventricular Function
  • Transgenes
  • Sarcoplasmic Reticulum
  • Rats
  • RNA, Messenger
  • Myocardium
  • Myocardial Contraction
  • Mice, Transgenic
  • Mice
  • Indoles
 

Citation

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He, H., Giordano, F. J., Hilal-Dandan, R., Choi, D. J., Rockman, H. A., McDonough, P. M., … Dillmann, W. H. (1997). Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation. J Clin Invest, 100(2), 380–389. https://doi.org/10.1172/JCI119544
He, H., F. J. Giordano, R. Hilal-Dandan, D. J. Choi, H. A. Rockman, P. M. McDonough, W. F. Bluhm, et al. “Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation.J Clin Invest 100, no. 2 (July 15, 1997): 380–89. https://doi.org/10.1172/JCI119544.
He H, Giordano FJ, Hilal-Dandan R, Choi DJ, Rockman HA, McDonough PM, et al. Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation. J Clin Invest. 1997 Jul 15;100(2):380–9.
He, H., et al. “Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation.J Clin Invest, vol. 100, no. 2, July 1997, pp. 380–89. Pubmed, doi:10.1172/JCI119544.
He H, Giordano FJ, Hilal-Dandan R, Choi DJ, Rockman HA, McDonough PM, Bluhm WF, Meyer M, Sayen MR, Swanson E, Dillmann WH. Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation. J Clin Invest. 1997 Jul 15;100(2):380–389.

Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

July 15, 1997

Volume

100

Issue

2

Start / End Page

380 / 389

Location

United States

Related Subject Headings

  • Ventricular Function
  • Transgenes
  • Sarcoplasmic Reticulum
  • Rats
  • RNA, Messenger
  • Myocardium
  • Myocardial Contraction
  • Mice, Transgenic
  • Mice
  • Indoles