Functional properties of transgenic mouse hearts overexpressing both calsequestrin and the Na(+)-Ca(2+) exchanger.

Linck B, Bokník P, Huke S, Kirchhefer U, Knapp J, Lüss H, Müller FU, Neumann J, Tanriseven Z, Vahlensieck U, Baba HA, Jones LR, Philipson KD, Schmitz W
J Pharmacol Exp Ther. 2000 294 (2): 648-57

PMID: 10900244

Overexpression of calsequestrin (CSQ) induces severe cardiac hypertrophy, whereas overexpression of Na(+)-Ca(2+) 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)-Ca(2+)-ATPase and phospholamban, proteins involved in the Ca(2+) uptake of the SR, were only increased in CSQ, indicating a possible influence of NCX in the regulation of SR-Ca(2+) uptake proteins. The Ca(2+) transients and the L-type Ca(2+) 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 Ca(2+) homeostasis.

MeSH Terms (23)

Animals Body Weight Caffeine Calcium Calcium-Transporting ATPases Calcium Channels, L-Type Calsequestrin Cardiomegaly Cytosol Female Gene Expression Heart Heart Rate In Vitro Techniques Male Mice Mice, Transgenic Myocardial Contraction Myocardium Organ Size RNA, Messenger Sarcoplasmic Reticulum Sodium-Calcium Exchanger

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