Impaired cardiac performance in heterozygous mice with a null mutation in the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) gene

Muthu Periasamy, Thomas D. Reed, Lynne H. Liu, Yong Ji, Evgeny Loukianov, Richard J. Paul, Michelle L. Nieman, Tara Riddle, John J. Duffy, Thomas C Doetschman, John N. Lorenz, Gary E. Shull

Research output: Contribution to journalArticle

198 Scopus citations

Abstract

The sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) gene encodes both SERCA2a, the cardiac sarcoplasmic reticulum Ca2+ pump, and SERCA2b, which is expressed in all tissues. To gain a better understanding of the physiological functions of SERCA2, we used gene targeting to develop a mouse in which the promoter and 5' end of the gene were eliminated. Mating of heterozygous mutant mice yielded wild-type and heterozygous offspring; homozygous mutants were not observed. RNase protection, Western blotting, and biochemical analysis of heart samples showed that SERCA2 mRNA was reduced by ~45% in heterozygous mutant hearts and that SERCA2 protein and maximal velocity of Ca2+ uptake into the sarcoplasmic reticulum were reduced by ~35%. Measurements of cardiovascular performance via transducers in the left ventricle and right femoral artery of the anesthetized mouse revealed reductions in mean arterial pressure, systolic ventricular pressure, and the absolute values of both positive and negative dP/dt in heterozygous mutants. These results demonstrate that two functional copies of the SERCA2 gene are required to maintain normal levels of SERCA2 mRNA, protein, and Ca2+ sequestering activity, and that the deficit in Ca2+ sequestering activity due to the loss of one copy of the SERCA2 gene impairs cardiac contractility and relaxation.

Original languageEnglish (US)
Pages (from-to)2556-2562
Number of pages7
JournalJournal of Biological Chemistry
Volume274
Issue number4
DOIs
Publication statusPublished - Jan 22 1999
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry

Cite this