title: Functional properties of transgenic mouse hearts overexpressing both calsequestrin and the Na(+)-Ca(2+) exchanger.
abstract: 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.
authors.affiliation: Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Münster, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Linck
authors.forename: P
authors.initials: P
authors.lastname: Bokník
authors.forename: S
authors.initials: S
authors.lastname: Huke
authors.forename: U
authors.initials: U
authors.lastname: Kirchhefer
authors.forename: J
authors.initials: J
authors.lastname: Knapp
authors.forename: H
authors.initials: H
authors.lastname: Lüss
authors.forename: F U
authors.initials: FU
authors.lastname: Müller
authors.forename: J
authors.initials: J
authors.lastname: Neumann
authors.forename: Z
authors.initials: Z
authors.lastname: Tanriseven
authors.forename: U
authors.initials: U
authors.lastname: Vahlensieck
authors.forename: H A
authors.initials: HA
authors.lastname: Baba
authors.forename: L R
authors.initials: LR
authors.lastname: Jones
authors.forename: K D
authors.initials: KD
authors.lastname: Philipson
authors.forename: W
authors.initials: W
authors.lastname: Schmitz
mesh_terms: 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
chemical_list: D020746:Calcium Channels, L-Type; D002155:Calsequestrin; D012333:RNA, Messenger; D019831:Sodium-Calcium Exchanger; D002110:Caffeine; D000252:Calcium-Transporting ATPases; D002118:Calcium