title: Sodium accumulation promotes diastolic dysfunction in end-stage heart failure following Serca2 knockout.
abstract: Alterations in trans-sarcolemmal and sarcoplasmic reticulum (SR) Ca(2+) fluxes may contribute to impaired cardiomyocyte contraction and relaxation in heart failure. We investigated the mechanisms underlying heart failure progression in mice with conditional, cardiomyocyte-specific excision of the SR Ca(2+)-ATPase (SERCA) gene. At 4 weeks following gene deletion (4-week KO) cardiac function remained near normal values. However, end-stage heart failure developed by 7 weeks (7-week KO) as systolic and diastolic performance declined. Contractions in isolated myocytes were reduced between 4- and 7-week KO, and relaxation was slowed. Ca(2+) transients were similarly altered. Reduction in Ca(2+) transient magnitude resulted from complete loss of SR Ca(2+) release between 4- and 7-week KO, due to loss of a small remaining pool of SERCA2. Declining SR Ca(2+) release was partly offset by increased L-type Ca(2+) current, which was facilitated by AP prolongation in 7-week KO. Ca(2+) entry via reverse-mode Na(+)-Ca(2+) exchange (NCX) was also enhanced. Up-regulation of NCX and plasma membrane Ca(2+)-ATPase increased Ca(2+) extrusion rates in 4-week KO. Diastolic dysfunction in 7-week KO resulted from further SERCA2 loss, but also impaired NCX-mediated Ca(2+) extrusion following Na(+) accumulation. Reduced Na(+)-K(+)-ATPase activity contributed to the Na(+) gain. Normalizing [Na(+)] by dialysis increased the Ca(2+) decline rate in 7-week KO beyond 4-week values. Thus, while SERCA2 loss promotes both systolic and diastolic dysfunction, Na(+) accumulation additionally impairs relaxation in this model. Our observations indicate that if cytosolic Na(+) gain is prevented, up-regulated Ca(2+) extrusion mechanisms can maintain near-normal diastolic function in the absence of SERCA2.
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital Ullevaal, 0407 Oslo, Norway. w.e.louch@medisin.uio.no
authors.forename: William E
authors.initials: WE
authors.lastname: Louch
authors.forename: Karina
authors.initials: K
authors.lastname: Hougen
authors.forename: Halvor K
authors.initials: HK
authors.lastname: Mørk
authors.forename: Fredrik
authors.initials: F
authors.lastname: Swift
authors.forename: Jan M
authors.initials: JM
authors.lastname: Aronsen
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.forename: Henrik M
authors.initials: HM
authors.lastname: Reims
authors.forename: Borghild
authors.initials: B
authors.lastname: Roald
authors.forename: Kristin B
authors.initials: KB
authors.lastname: Andersson
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
authors.forename: Ole M
authors.initials: OM
authors.lastname: Sejersted
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D003971:Diastole / Q000502:physiology*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000502:physiology*; D012720:Severity of Illness Index; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
chemical_list: D019831:Sodium-Calcium Exchanger; D012964:Sodium; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D000252:Calcium-Transporting ATPases; D002118:Calcium