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

The sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) gene encode s both SERCA2a, the cardiac sarcoplasmic reticulum Ca2+ pump, and SERCA2b, which is expressed in all tissues. To gain a better understanding of the ph ysiological 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 het erozygous mutant mice yielded wild-type and heterozygous offspring; homozyg ous mutants were not observed. RNase protection, Western blotting, and bioc hemical analysis of heart samples showed that SERCA2 mRNA was reduced by si milar to 45% in heterozygous mutant hearts and that SERCA2 protein and maxi mal velocity of Ca2+ uptake into the sarcoplasmic reticulum were reduced by similar to 35%, Measurements of cardiovascular performance via transducers in the left ventricle and right femoral artery of the anesthetized mouse r evealed reductions in mean arterial pressure, systolic ventricular pressure , and the absolute values of both positive and negative dP/dt in heterozygo us mutants. These results demonstrate that two functional copies of the SER CA2 gene are required to maintain normal levels of SERCA2 mRNA, protein, an d Ca2+ sequestering activity, and that the deficit in Ca2+ sequestering act ivity due to the loss of one copy of the SERCA2 gene impairs cardiac contra ctility and relaxation.