TY - JOUR T1 - Functional Properties of Transgenic Mouse Hearts Overexpressing Both Calsequestrin and the Na<sup>+</sup>-Ca<sup>2+</sup>Exchanger JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 648 LP - 657 VL - 294 IS - 2 AU - Bettina Linck AU - Peter Bokník AU - Sabine Huke AU - Uwe Kirchhefer AU - Jörg Knapp AU - Hartmut Lüss AU - Frank U. Müller AU - Joachim Neumann AU - Zahide Tanriseven AU - Ute Vahlensieck AU - Hideo A. Baba AU - Larry R. Jones AU - Kenneth D. Philipson AU - Wilhelm Schmitz Y1 - 2000/08/01 UR - http://jpet.aspetjournals.org/content/294/2/648.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -