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Life and death of a cardiac calcium spark.

ABSTRACT: Calcium sparks in cardiac myocytes are brief, localized calcium releases from the sarcoplasmic reticulum (SR) believed to be caused by locally regenerative calcium-induced calcium release (CICR) via couplons, clusters of ryanodine receptors (RyRs). How such regeneration is terminated is uncertain. We performed numerical simulations of an idealized stochastic model of spark production, assuming a RyR gating scheme with only two states (open and closed). Local depletion of calcium in the SR was inevitable during a spark, and this could terminate sparks by interrupting CICR, with or without assumed modulation of RyR gating by SR lumenal calcium. Spark termination by local SR depletion was not robust: under some conditions, sparks could be greatly and variably prolonged, terminating by stochastic attrition-a phenomenon we dub "spark metastability." Spark fluorescence rise time was not a good surrogate for the duration of calcium release. Using a highly simplified, deterministic model of the dynamics of a couplon, we show that spark metastability depends on the kinetic relationship of RyR gating and junctional SR refilling rates. The conditions for spark metastability resemble those produced by known mutations of RyR2 and CASQ2 that cause life-threatening triggered arrhythmias, and spark metastability may be mitigated by altering the kinetics of the RyR in a manner similar to the effects of drugs known to prevent those arrhythmias. The model was unable to explain the distributions of spark amplitudes and rise times seen in chemically skinned cat atrial myocytes, suggesting that such sparks may be more complex events involving heterogeneity of couplons or local propagation among sub-clusters of RyRs.

SUBMITTER: Stern MD

PROVIDER: S-EPMC3753601 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Life and death of a cardiac calcium spark.

Stern Michael D MD Ríos Eduardo E Maltsev Victor A VA

The Journal of general physiology 20130901 3

Calcium sparks in cardiac myocytes are brief, localized calcium releases from the sarcoplasmic reticulum (SR) believed to be caused by locally regenerative calcium-induced calcium release (CICR) via couplons, clusters of ryanodine receptors (RyRs). How such regeneration is terminated is uncertain. We performed numerical simulations of an idealized stochastic model of spark production, assuming a RyR gating scheme with only two states (open and closed). Local depletion of calcium in the SR was in ...[more]

PMID: 23980195

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Project description:Introduction: In ventricular myocytes, spontaneous release of calcium (Ca2+) from the sarcoplasmic reticulum via ryanodine receptors ("Ca2+ sparks") is acutely increased by stretch, due to a stretch-induced increase of reactive oxygen species (ROS). In acute regional ischemia there is stretch of ischemic tissue, along with an increase in Ca2+ spark rate and ROS production, each of which has been implicated in arrhythmogenesis. Yet, whether there is an impact of ischemia on the stretch-induced increase in Ca2+ sparks and ROS has not been investigated. We hypothesized that ischemia would enhance the increase of Ca2+ sparks and ROS that occurs with stretch. Methods: Isolated ventricular myocytes from mice (male, C57BL/6J) were loaded with fluorescent dye to detect Ca2+ sparks (4.6 ?M Fluo-4, 10 min) or ROS (1 ?M DCF, 20 min), exposed to normal Tyrode (NT) or simulated ischemia (SI) solution (hyperkalemia [15 mM potassium], acidosis [6.5 pH], and metabolic inhibition [1 mM sodium cyanide, 20 mM 2-deoxyglucose]), and subjected to sustained stretch by the carbon fiber technique (~10% increase in sarcomere length, 15 s). Ca2+ spark rate and rate of ROS production were measured by confocal microscopy. Results: Baseline Ca2+ spark rate was greater in SI (2.54 ± 0.11 sparks·s-1·100 ?m-2; n = 103 cells, N = 10 mice) than NT (0.29 ± 0.05 sparks·s-1·100 ?m-2; n = 33 cells, N = 9 mice; p < 0.0001). Stretch resulted in an acute increase in Ca2+ spark rate in both SI (3.03 ± 0.13 sparks·s-1·100 ?m-2; p < 0.0001) and NT (0.49 ± 0.07 sparks·s-1·100 ?m-2; p < 0.0001), with the increase in SI being greater than NT (+0.49 ± 0.04 vs. +0.20 ± 0.04 sparks·s-1·100 ?m-2; p < 0.0001). Baseline rate of ROS production was also greater in SI (1.01 ± 0.01 normalized slope; n = 11, N = 8 mice) than NT (0.98 ± 0.01 normalized slope; n = 12, N = 4 mice; p < 0.05), but there was an acute increase with stretch only in SI (+12.5 ± 2.6%; p < 0.001). Conclusion: Ischemia enhances the stretch-induced increase of Ca2+ sparks in ventricular myocytes, with an associated enhancement of stretch-induced ROS production. This effect may be important for premature excitation and/or in the development of an arrhythmogenic substrate in acute regional ischemia.

Project description:Lethal ventricular arrhythmia‑sudden cardiac death (LVA‑SCD) occurs frequently during the early stage of myocardial ischemia (MI). However, the mechanism underlying higher LVA‑SCD incidence is still poorly understood. The present study aimed to explore the role of mitochondrial reactive oxygen species (mROS) and Ca2+ crosstalk in promoting LVA‑SCD in early MI. RyR2 S2814A mice and their wild‑type littermates were used. MitoTEMPO was applied to scavenge mitochondrial ROS (mROS). Mice were subjected to severe MI and the occurrence of LVA‑SCD was evaluated. Levels of mitochondrial ROS and calcium (mitoCa2+), cytosolic ROS (cytoROS), and calcium (cytoCa2+), RyR2 Ser‑2814 phosphorylation, CaMKII Met‑282 oxidation, mitochondrial membrane potential (MMP), and glutathione/oxidized glutathione (GSH/GSSG) ratio in the myocardia were detected. Dynamic changes in mROS after hypoxia were investigated using H9c2 cells. Moreover, the myocardial phosphoproteome was analyzed to explore the related mechanisms facilitating mROS‑Ca2+ crosstalk and LVA‑SCD. There was a high incidence (~33.9%) of LVA‑SCD in early MI. Mice who underwent SCD displayed notably elevated levels of myocardial ROS and mROS, and the latter was validated in H9c2 cells. These mice also demonstrated overloads of cytoplasmic and mitochondrial Ca2+, decreased MMP and reduced GSH/GSSG ratio, upregulated RyR2‑S2814 phosphorylation and CaMKII‑M282 oxidation and transient hyperphosphorylation of mitochondrial proteomes in the myocardium. mROS‑specific scavenging by a mitochondria‑targeted antioxidant agent (MitoTEMPO) corrected these SCD‑induced alterations. S2814A mice with a genetically inactivated CaMKII phosphorylation site in RyR2 exhibited decreased overloads in cytoplasmic and mitochondrial Ca2+ and demonstrated similar effects as MitoTEMPO to correct SCD‑induced changes and prevent SCD post‑MI. The data confirmed crosstalk between mROS and Ca2+ in promoting LVA‑SCD. Therefore, we provided evidence that there is a higher incidence of LVA‑SCD in early MI, which may be attributed to a positive feedback loop between mROS and Ca2+ imbalance.

Dataset Information

Life and death of a cardiac calcium spark.

Publications

Life and death of a cardiac calcium spark.

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