Functional properties of transgenic mouse hearts overexpressing both calsequestrin and the Na(+)-Ca(2+) exchanger.
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.
Linck
B
B
Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Münster, Germany.
Bokník
P
P
Huke
S
S
Kirchhefer
U
U
Knapp
J
J
Lüss
H
H
Müller
F U
FU
Neumann
J
J
Tanriseven
Z
Z
Vahlensieck
U
U
Baba
H A
HA
Jones
L R
LR
Philipson
K D
KD
Schmitz
W
W
D000818:Animals; D001835:Body Weight / Q000502:physiology; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002155:Calsequestrin / Q000096:biosynthesis* / Q000235:genetics; D006332:Cardiomegaly / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006321:Heart / Q000033:anatomy & histology / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009929:Organ Size / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000096:biosynthesis* / Q000235:genetics
D020746:Calcium Channels, L-Type; D002155:Calsequestrin; D012333:RNA, Messenger; D019831:Sodium-Calcium Exchanger; D002110:Caffeine; D000252:Calcium-Transporting ATPases; D002118:Calcium