title: Sodium accumulation in SERCA knockout-induced heart failure.
abstract: In cardiomyocytes, a major decrease in the level of sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) can severely impair systolic and diastolic functions. In mice with cardiomyocyte-specific conditional excision of the Serca2 gene (SERCA2 KO), end-stage heart failure developed between four and seven weeks after gene deletion combined with [Na(+)](i) elevation and intracellular acidosis. In this study, to investigate the underpinning changes in Ca(2+) dynamics and metabolic homeostasis, we developed data-driven mathematical models of Ca(2+) dynamics in the ventricular myocytes of the control, four-week, and seven-week SERCA2 knockout (KO) mice. The seven-week KO model showed that elevated [Na(+)](i) was due to increased Na(+) influxes through the Na(+)/Ca(2+) exchanger (NCX) and the Na(+)/H(+) exchanger, with the latter exacerbated by intracellular acidosis. Furthermore, NCX upregulation in the seven-week KO model resulted in increased ATP consumption for ion transport. Na(+) accumulation in the SERCA KO due to NCX upregulation and intracellular acidosis potentially play a role in the development of heart failure, by initiating a reinforcing cycle involving: a mismatch between ATP demand and supply; an increasingly compromised metabolism; a decreased pH(i); and, finally, an even greater [Na(+)](i) elevation.
authors: Department of Computer Science, University of Oxford, Oxford, UK.
authors: Liren
authors: L
authors: Li
authors: William E
authors: WE
authors: Louch
authors: Steven A
authors: SA
authors: Niederer
authors: Jan M
authors: JM
authors: Aronsen
authors: Geir
authors: G
authors: Christensen
authors: Ole M
authors: OM
authors: Sejersted
authors: Nicolas P
authors: NP
authors: Smith
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003198:Computer Simulation; D006333:Heart Failure / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*
chemical_list: D012964:Sodium; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium