Vol. 294, Issue 2, 648-657, August 2000

Functional Properties of Transgenic Mouse Hearts Overexpressing Both Calsequestrin and the Na⁺-Ca²⁺ Exchanger¹

Bettina Linck, Peter Bokník, Sabine Huke, Uwe Kirchhefer, Jörg Knapp, Hartmut Lüss, Frank U. Müller, Joachim Neumann, Zahide Tanriseven, Ute Vahlensieck, Hideo A. Baba, Larry R. Jones, Kenneth D. Philipson and Wilhelm Schmitz

Institut für Pharmakologie und Toxikologie (B.L., P.B., S.H., U.K., J.K., H.L., F.U.M., J.N., Z.T., U.V., W.S.) and Institut für Pathologie (H.A.B.), Westfälische Wilhelms-Universität, Münster, Germany; Krannert Institute of Cardiology and Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana (L.R.J.); and Department of Physiology and Medicine and Cardiovascular Research Laboratories, University of California, Los Angeles, School of Medicine, California (K.D.P.)

Overexpression of calsequestrin (CSQ) induces severe cardiac hypertrophy, whereas overexpression of Na⁺-Ca²⁺ exchanger (NCX) does not affect cardiac weight. To investigate a possible beneficial effect of NCX in hypertrophy, we produced transgenic mice overexpressing both NCX and CSQ (NCX/CSQ). Surprisingly, these mice developed severe heart failure. The heart/body weight ratio was enhanced and the mRNA expression of ANF, as a marker of hypertrophy, was highest in double transgenic mice. In isolated muscle strips, the basal relaxation time was prolonged in CSQ and NCX/CSQ mice. Moreover, in the presence of caffeine, force of contraction was increased only in CSQ and NCX/CSQ and was accompanied by elevated diastolic tension. In some respects, however, additional overexpression of NCX altered the CSQ phenotype into the wild-type phenotype. The expression of sarcoplasmic reticulum (SR)-Ca²⁺-ATPase and phospholamban, proteins involved in the Ca²⁺ uptake of the SR, were only increased in CSQ, indicating a possible influence of NCX in the regulation of SR-Ca²⁺ uptake proteins. The Ca²⁺ transients and the L-type Ca²⁺ currents in the presence of caffeine were very large in CSQ, but smaller increases were noted in double transgenic mice. Therefore, the successful co-overexpression of CSQ and NCX in these mice provides a novel model in which to investigate the interaction of proteins tightly linked to maintain Ca²⁺ homeostasis.