Abstract
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.
Footnotes
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Send reprint requests to: Dr. Bettina Linck, Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Domagkstr. 12, D-48129 Münster, Germany
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↵1 This work was supported by National Heart, Lung, and Blood Institute Grants HL06308 and HL48509 and the Deutsche Forschungsgemeinschaft (DFG).
- Abbreviations:
- SR
- sarcoplasmic reticulum
- SERCA
- sarcoplasmic reticulum-Ca2+-ATPase
- CSQ
- calsequestrin
- NCX
- Na+-Ca2+ exchanger
- PLB
- phospholamban
- TPT
- time to peak tension
- RT
- relaxation time
- TCT
- total contraction time
- TnI
- troponin inhibitor
- ANF
- atrial natruretic factor
- SSC
- standard saline citrate
- TEA
- tetraethylammonium
- [Ca]i
- intracellular Ca2+ concentration
- MOPS
- 4-morpholinepropanesulfonic acid
- Received November 29, 1999.
- Accepted April 17, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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