Integrative analysis of calcium signalling in cardiac muscle

Trafford, Andrew; Díaz, M. E.; O’Neill, Stephen; Eisner, David

doi:10.2741/trafford

Cited by 38 publications

(28 citation statements)

References 52 publications

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“…Why Pln -/-mice do not develop cardiac dysfunction while the β2a mice studied here had profound cardiac abnormalities is not entirely clear, but could be related to adaptive reductions in Ca 2+ influx through the LTCC or increases in Ca 2+ efflux via the NCX. These adaptive changes in Ca 2+ handling could lead to a scenario in which the enhanced SERCA2 activity in Pln -/-mice produces total cytosolic Ca 2+ levels averaged across systole and diastole that are not appreciably different from wild type (39). However, human heart failure is characterized by increased LTCC activity (30,31) and prolongation in the action potential (16), states that tend to increase Ca 2+ influx.…”

Section: Discussionmentioning

confidence: 99%

“…Changes in the amount of Ca 2+ within adult ventricular myocytes needed to alter contractility are primarily accomplished by increasing LTCC-mediated Ca 2+ fluxes across the sarcolemma. Physiologically, transient increases in cardiac function during exercise occur via catecholamine-regulated increases in Ca 2+ influx through the LTCC, which increases SR Ca 2+ loading, the magnitude of the Ca 2+ transient, and cardiac contractility (39). In the new steady state this increased Ca 2+ influx and SR Ca 2+ loading is balanced by increased Ca 2+ efflux via the NCX or by the plasma membrane Ca 2+ ATPase pump (39).…”

Section: Discussionmentioning

confidence: 99%

“…Physiologically, transient increases in cardiac function during exercise occur via catecholamine-regulated increases in Ca 2+ influx through the LTCC, which increases SR Ca 2+ loading, the magnitude of the Ca 2+ transient, and cardiac contractility (39). In the new steady state this increased Ca 2+ influx and SR Ca 2+ loading is balanced by increased Ca 2+ efflux via the NCX or by the plasma membrane Ca 2+ ATPase pump (39). However, if Ca 2+ influx is persistently activated or if Ca 2+ removal systems are persistently compromised, as can occur in heart failure (40), dysfunctional Ca 2+ handling can induce Ca 2+ overload.…”

Section: Discussionmentioning

confidence: 99%

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Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure

Nakayama¹,

Chen²,

Baines³

et al. 2007

J. Clin. Invest.

377

361

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Loss of cardiac myocytes in heart failure is thought to occur largely through an apoptotic process. Here we show that heart failure can also be precipitated through myocyte necrosis associated with Ca 2+ overload. Inducible transgenic mice with enhanced sarcolemmal L-type Ca 2+ channel (LTCC) activity showed progressive myocyte necrosis that led to pump dysfunction and premature death, effects that were dramatically enhanced by acute stimulation of β-adrenergic receptors. Enhanced Ca 2+ influx-induced cellular necrosis and cardiomyopathy was prevented with either LTCC blockers or β-adrenergic receptor antagonists, demonstrating a proximal relationship among β-adrenergic receptor function, Ca 2+ handling, and heart failure progression through necrotic cell loss. Mechanistically, loss of cyclophilin D, a regulator of the mitochondrial permeability transition pore that underpins necrosis, blocked Ca 2+ influx-induced necrosis of myocytes, heart failure, and isoproterenol-induced premature death. In contrast, overexpression of the antiapoptotic factor Bcl-2 was ineffective in mitigating heart failure and death associated with excess Ca 2+ influx and acute β-adrenergic receptor stimulation. This paradigm of mitochondrial-and necrosis-dependent heart failure was also observed in other mouse models of disease, which supports the concept that heart failure is a pleiotropic disorder that involves not only apoptosis, but also necrotic loss of myocytes in association with dysregulated Ca 2+ handling and β-adrenergic receptor signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure

Nakayama¹,

Chen²,

Baines³

et al. 2007

J. Clin. Invest.

377

361

View full text Add to dashboard Cite

show abstract

“…Therefore, among the previously reported S100A1 effects on Ca 2+ signaling a reduction of the SR Ca 2+ leak at rest is the most likely explanation for these findings, and is consistent with the reported inhibition of RyR2 by S100A1 at diastolic [Ca 2+ ] i . Because of the autoregulatory features of CICR for varying Ca 2+ triggers and SR Ca 2+ releases, it is expected that, in the steady state, the total amount of Ca 2+ released from the SR self-adjusts and does not change much (Trafford et al 2002). A significant SERCA2a stimulation by S100A1 seems unlikely under our conditions, as the Ca 2+ transients did not decay faster in the presence of the protein.…”

Section: Acute Interaction Of S100a With Ca 2+ Signaling Proteinsmentioning

confidence: 79%

Ca2+ signaling in mouse cardiomyocytes with ablated S100A1 protein

Gusev

Ackermann

Heizmann

et al. 2009

gpb

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Abstract. S100A1 is a Ca 2+ -binding protein expressed at high levels in the myocardium. It is thought to modulate the Ca 2+ sensitivity of the sarcoplasmic reticulum (SR) Ca 2+ release channels (ryanodine receptors or RyRs) and its expression has been shown to be down regulated in various heart diseases. In this study we used S100A1 knock-out (KO) mice to investigate the consequences of chronic S100A1 deficiency on Ca 2+ cycling in ventricular cardiomyocytes. Confocal Ca 2+ imaging showed that fieldstimulated KO myocytes had near normal Ca 2+ signaling under control conditions but a blunted response to β-adrenergic stimulation with 1 μmol/l isoproterenol (ISO). Voltage-clamp experiments revealed that S100A1-deficient cardiomyocytes have elevated I Ca under basal conditions. This larger Ca 2+ influx was accompanied by augmented Ca 2+ transients and elevated SR Ca 2+ content, without changes in macroscopic excitation-contraction coupling gain, which suggests impaired fractional Ca 2+ release. Exposure of KO and WT cells to ISO led to similar maximal I Ca . Thus, the stimulation of the I Ca was less pronounced in KO cardiomyocytes, suggesting that changes in basal I Ca could underlie the reduced β-adrenergic response. Taken together, our findings indicate that chronic absence of S100A1 results in enhanced L-type Ca 2+ channel activity combined with a blunted SR Ca 2+ release amplification. These findings may have implications in a variety of cardiac pathologies where abnormal RyR Ca 2+ sensitivity or reduced S100A1 levels have been described.

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“…Thus, the latter amount would be equivalent to ∫J SR dt during the SS twitch. Previous studies support the validity of such an assumption (Delbridge et al 1996;Trafford et al 2002). FR at the SS twitch was considered as the ratio of ∫J SR dt and the SR Ca 2+ content.…”

Section: + Flux Approachmentioning

confidence: 93%