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 over-expression 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.
|Original language||English (US)|
|Number of pages||10|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Aug 1 2000|
ASJC Scopus subject areas
- Molecular Medicine