Slow Ca2+ sparks de-synchronize Ca2+ release in failing cardiomyocytes: Evidence for altered configuration of Ca2+ release units?

Louch, William E.; Hake, Johan; Mørk, Halvor K.; Hougen, Karina; Skrbic, Biljana; Ursu, Daniel; Tønnessen, Theis; Sjaastad, Ivar; Sejersted, Ole M.

doi:10.1016/j.yjmcc.2013.01.014

Cited by 57 publications

(78 citation statements)

References 48 publications

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“…For TT alterations to have a clear effect in Ca 2+ signaling and heart function, TT density has been reported to decrease by ~30-40% in human HF, pig and rat hypertrophy and HF models [5,6], and ~24% in a tachypacing dog model [33]. Others have reported large TT disarrangements (assessed as ~40% decrease in overall TT integrity) [14] or were accompanied by major disruption in their distribution [9,13] in TAC rodent HF models and in SHRs with HF [4,11]. Nevertheless, our data confirm that TT remodeling occurs in compensated cardiac hypertrophy, appearing as early as six weeks after AAC, preceding [4-6, 11, 14, 33, 48], and the small difference that we found between both cell types could have not resulted from differential membrane affinity for the fluorophore or from differences in membrane potential, since both cell types were in resting conditions and were quiescent, as evidenced by the lack of motion artifacts, which is essential for acquiring full z-stacks of two-dimensional images.…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that in hypertrophied cells from HF, the transverse tubules (TT), the highly specialized system of sarcolemmal invaginations in ventricular myocytes, undergoes remodeling, which includes disarrangement or disappearance of tubules [4][5][6][7][8][9][10][11]. Since TT contains most of the L-type Ca 2+ channels, essential for the excitation-contraction coupling (ECC) [12], TT remodeling in HF affects ECC by delaying recruitment of clusters of Ca 2+ release channels (RyR) of the sarcoplasmic reticulum (SR) by the sarcolemmal Ca 2+ current, or failing to activate them [4,5,8,13]. Overt TT remodeling affects the spatial and temporal homogeneity of the systolic Ca 2+ transient, which appears with blunted amplitude and slower time course, and all these impair the magnitude and rate of force development [4,5,8,11].…”

Section: Introductionmentioning

confidence: 99%

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Changes in T-Tubules and Sarcoplasmic Reticulum in Ventricular Myocytes in Early Cardiac Hypertrophy in a Pressure Overload Rat Model

Pérez-Treviño

Borja-Villa

et al. 2015

Cell Physiol Biochem

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Background/Aims: Pressure-overload (PO) causes cardiac hypertrophy (CH), and eventually leads to heart failure (HF). HF ventricular myocytes present transverse-tubules (TT) loss or disarrangement and decreased sarcoplasmic reticulum (SR) density, and both contribute to altered Ca²⁺ signaling and heart dysfunction. It has been shown that TT remodeling precedes HF, however, it is unknown whether SR structural and functional remodeling also starts early in CH. Methods: Using confocal microscopy, we assessed TT (with Di-8-ANNEPS) and SR (with SR-trapped Mag-Fluo-4) densities, as well as SR fluorophore diffusion (fluorescence recovery after photobleach; FRAP), cytosolic Ca²⁺ signaling and ex vivo cardiac performance in a PO rat hypertrophy model induced by abdominal aortic constriction (at 6 weeks). Results: Rats developed CH, while cardiac performance, basal and upon β-adrenergic stimulation, remained unaltered. TT density decreased by ∼14%, without spatial disarrangement, while SR density decreased by ∼7%. More important, FRAP was ∼30% slower, but with similar maximum recovery, suggesting decreased SR interconnectivity. Systolic and diastolic Ca²⁺ signaling and SR Ca²⁺ content were unaltered. Conclusion: SR remodeling is an early CH event, similar to TT remodeling, appearing during compensated hypertrophy. Nevertheless, myocytes can withstand those moderate structural changes in SR and TT, preserving normal Ca²⁺ signaling and contractility.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Changes in T-Tubules and Sarcoplasmic Reticulum in Ventricular Myocytes in Early Cardiac Hypertrophy in a Pressure Overload Rat Model

Pérez-Treviño

Borja-Villa

et al. 2015

Cell Physiol Biochem

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“…Thus, the contraction of the neighbouring sarcomere is likely inhomogeneous, thereby reducing the speed of myocardial contractility and cardiac contractility. 12 Various factors desynchronized Ca 2+ cycling, including loss and abnormality of T tubules, 13 immaturity of RYR2, variability in Ca 2+ sparks kinetics, 14 and the AP shape. 15 However, our study did not include related research on these corresponding experimental conditions.…”

Section: Dyssynchronous Ca 21 Homeostasis and Myocardial Contractilitymentioning

confidence: 99%

Effects of levosimendan on calcium transient in norepinephrine-cultured neonatal rat ventricular myocytes

et al. 2016

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This study aimed to explore the changes in calcium transient in the development of heart failure and the effects of levosimendan (LeV) on intracellular calcium dynamics. Cultured neonatal rat ventricular myocytes were divided into four groups: normal, norepinephrine (NE) only (10 mmol/L), NE + LeV1 (0.1 mmol/L), and NE + LeV2 (1 mmol/L). The calcium transients of the myocytes loaded with Fluo-3/AM were observed using a laser scanning confocal microscope. Compared with the control group, the calcium wave in the NE group dispersed, propagated slowly, and exhibited dyssynchrony of Ca 2+ release. Norepinephrine accelerated the beating rate of the cultured myocytes, decreased the systolic peak Ca 2+ , and increased the time to peak (Ttp) and decay time (Tau) of calcium transient. Levosimendan increased the synchrony of calcium transient, and reduced Ttp and Tau. In contrast, LeV did not affect the beating rate and systolic peak Ca 2+ . Both NE-only-and LeV-treated groups did not affect resting Ca 2+ and calcium transient amplitude of the myocytes. The currents from L-type calcium channel currents did not differ among the groups. Both NE and LeV shortened the action potential duration, but the effect of the latter was more serious than that of the former. Western blot results showed that the sarco/endoplasmic reticulum Ca 2+ -ATPase 2 (SERCA2) expression decreased in the NE group but increased in the LeV groups. The sodium-calcium exchanger 1 (NCX1) expression increased in the NE group but decreased in the LeV groups. Long-term exposure to NE decreased myocardial contractility by reducing the peak Ca 2+ of calcium transient and by prolonging and disrupting the conduction of calcium waves. Levosimendan elicits a positive inotropic effect by accelerating the velocity of calcium signal propagation and synchronizing calcium release without increasing calcium influx.

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“…The progression of heart failure, as an example, is often accompanied by intracellular remodeling that decouples key calcium channels like the L-type calcium channel (LCC) and the Ryanodine receptor (RyR); 53 as a result, the ability of the cell to generate an efficacious, synchronous response is compromised, which ultimately deprecates the integrity of contractile force generation. 54 It is certainly possible, however, that strong intermolecular interactions and in particular electrostatic interactions with crowders may further suppress apparent intracellular diffusion rates. 8,55 In this regard, decreased pH resulting from ischemia reperfusion 56 or alterations in intracellular ionic strength are both expected to influence the strength of electrostatic factors governing diffusion.…”

Section: Computational Evidence For Amplitude Modulation In "Compamentioning

confidence: 99%

Enzyme localization, crowding, and buffers collectively modulate diffusion-influenced signal transduction: Insights from continuum diffusion modeling

Kekenes‐Huskey

Eun

McCammon

2015

The Journal of Chemical Physics

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Biochemical reaction networks consisting of coupled enzymes connect substrate signaling events with biological function. Substrates involved in these reactions can be strongly influenced by diffusion "barriers" arising from impenetrable cellular structures and macromolecules, as well as interactions with biomolecules, especially within crowded environments. For diffusion-influenced reactions, the spatial organization of diffusion barriers arising from intracellular structures, non-specific crowders, and specific-binders (buffers) strongly controls the temporal and spatial reaction kinetics. In this study, we use two prototypical biochemical reactions, a Goodwin oscillator, and a reaction with a periodic source/sink term to examine how a diffusion barrier that partitions substrates controls reaction behavior. Namely, we examine how conditions representative of a densely packed cytosol, including reduced accessible volume fraction, non-specific interactions, and buffers, impede diffusion over nanometer length-scales. We find that diffusion barriers can modulate the frequencies and amplitudes of coupled diffusion-influenced reaction networks, as well as give rise to "compartments" of decoupled reactant populations. These effects appear to be intensified in the presence of buffers localized to the diffusion barrier. These findings have strong implications for the role of the cellular environment in tuning the dynamics of signaling pathways. C 2015 AIP Publishing LLC. [http://dx

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Slow Ca2+ sparks de-synchronize Ca2+ release in failing cardiomyocytes: Evidence for altered configuration of Ca2+ release units?

Cited by 57 publications

References 48 publications

Changes in T-Tubules and Sarcoplasmic Reticulum in Ventricular Myocytes in Early Cardiac Hypertrophy in a Pressure Overload Rat Model

Changes in T-Tubules and Sarcoplasmic Reticulum in Ventricular Myocytes in Early Cardiac Hypertrophy in a Pressure Overload Rat Model

Effects of levosimendan on calcium transient in norepinephrine-cultured neonatal rat ventricular myocytes

Enzyme localization, crowding, and buffers collectively modulate diffusion-influenced signal transduction: Insights from continuum diffusion modeling

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