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Beta-adrenergic stimulation maintains cardiac function in Serca2 knockout mice.

ABSTRACT: Previous studies on Serca2 knockout (KO) mice showed that cardiac function is sustained in vivo for several weeks after knockout, whereas SERCA protein levels decrease and calcium dynamics are significantly impaired. In this study, we reconcile observed cellular and organ level contractile function using a cardiac multiscale model. We identified and quantified the changes in cellular function that are both consistent with observations and able to compensate for the decrease in SERCA. Calcium transients were used as input for multiscale computational simulations to predict whole-organ response. Although this response matched experimental pressure-volume (PV) measurements in healthy mice, the reduced magnitude calcium transients observed in KO cells were insufficient to trigger ventricular ejection. To replicate the effects of elevated catecholamine levels observed in vivo, cells were treated with isoproterenol. Incorporation of the resulting measured ?-adrenergically stimulated calcium transients into the model resulted in a close match with experimental PV loops. Changes in myofilament properties, when considered in isolation, were not able to increase tension development to levels consistent with measurements, further confirming the necessity of a high ?-adrenergic state. Modeling additionally indicated that increased venous return observed in the KO mice helps maintain a high ejection fraction via the Frank-Starling effect. Our study shows that increased ?-adrenergic stimulation is a potentially highly significant compensatory mechanism by which cardiac function is maintained in Serca2 KO mice, producing the increases in both systolic and diastolic calcium, consistent with the observed contractile function observed in experimental PV measurements.

SUBMITTER: Land S

PROVIDER: S-EPMC3602781 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Beta-adrenergic stimulation maintains cardiac function in Serca2 knockout mice.

Land Sander S Louch William E WE Niederer Steven A SA Aronsen Jan Magnus JM Christensen Geir G Sjaastad Ivar I Sejersted Ole M OM Smith Nicolas P NP

Biophysical journal 20130319 6

Previous studies on Serca2 knockout (KO) mice showed that cardiac function is sustained in vivo for several weeks after knockout, whereas SERCA protein levels decrease and calcium dynamics are significantly impaired. In this study, we reconcile observed cellular and organ level contractile function using a cardiac multiscale model. We identified and quantified the changes in cellular function that are both consistent with observations and able to compensate for the decrease in SERCA. Calcium tra ...[more]

PMID: 23528094

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Project description:We describe a simulation study of Ca²(+) dynamics in mice with cardiomyocyte-specific conditional excision of the sarco(endo)plasmic reticulum calcium ATPase (SERCA) gene, using an experimental data-driven biophysically-based modeling framework. Previously, we reported a moderately impaired heart function measured in mice at 4 weeks after SERCA2 gene deletion (knockout (KO)), along with a >95% reduction in the level of SERCA2 protein. We also reported enhanced Ca²(+) flux through the L-type Ca²(+) channels and the Na(+)/Ca²(+) exchanger in ventricular myocytes isolated from these mice, compared to the control Serca2(flox/flox) mice (flox-flox (FF)). In the current study, a mathematical model-based analysis was applied to enable further quantitative investigation into changes in the Ca²(+) handling mechanisms in these KO cardiomyocytes. Model parameterization based on a wide range of experimental measurements showed a 67% reduction in SERCA activity and an over threefold increase in the activity of the Na(+)/Ca²(+) exchanger. The FF and KO models were then validated against experimentally measured [Ca²(+)](i) transients and experimentally estimated sarco(endo)plasmic reticulum (SR) function. Simulation results were in quantitative agreement with experimental measurements, confirming that sustained [Ca²(+)](i) transients could be maintained in the KO cardiomyocytes despite severely impaired SERCA function. In silico analysis shows that diastolic [Ca²(+)](i) rises sharply with progressive reductions in SERCA activity at physiologically relevant pacing frequencies. Furthermore, an analysis of the roles of the compensatory mechanisms revealed that the major combined effect of the compensatory mechanisms is to lower diastolic [Ca²(+)](i). Finally, by using a comprehensive sensitivity analysis of the role of all cellular calcium handling mechanisms, we show that the combination of upregulation of the Na(+)/Ca²(+) exchanger and increased L-type Ca²(+) current is the most effective means to maintain diastolic and systolic calcium levels after loss of SERCA function.

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Beta-adrenergic stimulation maintains cardiac function in Serca2 knockout mice.

Publications

Beta-adrenergic stimulation maintains cardiac function in Serca2 knockout mice.

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