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Sorcin ablation plus ?-adrenergic stimulation generate an arrhythmogenic substrate in mouse ventricular myocytes.

ABSTRACT: Sorcin, a penta-EF hand Ca2+-binding protein expressed in cardiomyocytes, is known to interact with ryanodine receptors and other Ca2+ regulatory proteins. To investigate sorcin's influence on cardiac excitation-contraction coupling and its role in the development of cardiac malfunctions, we generated a sorcin knockout (KO) mouse model. Sorcin KO mice presented ventricular arrhythmia and sudden death when challenged by acute stress induced by isoproterenol plus caffeine. Chronic stress, which was induced by transverse aortic constriction, significantly decreased the survival rate of sorcin KO mice. Under isoproterenol stimulation, spontaneous Ca2+ release events were frequently observed in sorcin KO cardiomyocytes. Sorcin KO hearts of adult, but not young mice developed overexpression of L-type Ca2+ channel and Na+-Ca2+ exchanger, which enhanced ICa and INCX. Consequently, spontaneous Ca2+ release events in sorcin KO cardiomyocytes were more likely to induce arrhythmogenic delayed afterdepolarizations. Our study demonstrates sorcin deficiency may trigger cardiac ventricular arrhythmias due to Ca2+ disturbances, and evidences the critical role of sorcin in maintaining Ca2+ homeostasis, especially during the adrenergic response of the heart.

SUBMITTER: Chen X

PROVIDER: S-EPMC5800963 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Sorcin ablation plus β-adrenergic stimulation generate an arrhythmogenic substrate in mouse ventricular myocytes.

Chen Xi X Weber Craig C Farrell Emily T ET Alvarado Francisco J FJ Zhao Yan-Ting YT Gómez Ana M AM Valdivia Héctor H HH

Journal of molecular and cellular cardiology 20171122

Sorcin, a penta-EF hand Ca<sup>2+</sup>-binding protein expressed in cardiomyocytes, is known to interact with ryanodine receptors and other Ca<sup>2+</sup> regulatory proteins. To investigate sorcin's influence on cardiac excitation-contraction coupling and its role in the development of cardiac malfunctions, we generated a sorcin knockout (KO) mouse model. Sorcin KO mice presented ventricular arrhythmia and sudden death when challenged by acute stress induced by isoproterenol plus caffeine. Ch ...[more]

PMID: 29174767

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Project description:Rationaleβ-Adrenergic receptor stimulation produces sarcoplasmic reticulum Ca(2+) overload and delayed afterdepolarizations in isolated ventricular myocytes. How delayed afterdepolarizations are synchronized to overcome the source-sink mismatch and produce focal arrhythmia in the intact heart remains unknown.ObjectiveTo determine whether local β-adrenergic receptor stimulation produces spatiotemporal synchronization of delayed afterdepolarizations and to examine the effects of tissue geometry and cell-cell coupling on the induction of focal arrhythmia.Methods and resultsSimultaneous optical mapping of transmembrane potential and Ca(2+) transients was performed in normal rabbit hearts during subepicardial injections (50 μL) of norepinephrine (NE) or control (normal Tyrode's solution). Local NE produced premature ventricular complexes (PVCs) from the injection site that were dose-dependent (low-dose [30-60 μmol/L], 0.45±0.62 PVCs per injection; high-dose [125-250 μmol/L], 1.33±1.46 PVCs per injection; P<0.0001) and were inhibited by propranolol. NE-induced PVCs exhibited abnormal voltage-Ca(2+) delay at the initiation site and were inhibited by either sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase inhibition or reduced perfusate [Ca(2+)], which indicates a Ca(2+)-mediated mechanism. NE-induced PVCs were more common at right ventricular than at left ventricular sites (1.48±1.50 versus 0.55±0.89, P<0.01), and this was unchanged after chemical ablation of endocardial Purkinje fibers, which suggests that source-sink interactions may contribute to the greater propensity to right ventricular PVCs. Partial gap junction uncoupling with carbenoxolone (25 μmol/L) increased focal activity (2.18±1.43 versus 1.33±1.46 PVCs per injection, P<0.05), which further supports source-sink balance as a critical mediator of Ca(2+)-induced PVCs.ConclusionsThese data provide the first experimental demonstration that localized β-adrenergic receptor stimulation produces spatiotemporal synchronization of sarcoplasmic reticulum Ca(2+) overload and release in the intact heart and highlight the critical nature of source-sink balance in initiating focal arrhythmias.

Project description:The ?1-adrenergic signaling system plays an important role in the functioning of cardiac cells. Experimental data shows that the activation of this system produces inotropy, lusitropy, and chronotropy in the heart, such as increased magnitude and relaxation rates of [Ca(2+)]i transients and contraction force, and increased heart rhythm. However, excessive stimulation of ?1-adrenergic receptors leads to heart dysfunction and heart failure. In this paper, a comprehensive, experimentally based mathematical model of the ?1-adrenergic signaling system for mouse ventricular myocytes is developed, which includes major subcellular functional compartments (caveolae, extracaveolae, and cytosol). The model describes biochemical reactions that occur during stimulation of ?1-adrenoceptors, changes in ionic currents, and modifications of Ca(2+) handling system. Simulations describe the dynamics of major signaling molecules, such as cyclic AMP and protein kinase A, in different subcellular compartments; the effects of inhibition of phosphodiesterases on cAMP production; kinetics and magnitudes of phosphorylation of ion channels, transporters, and Ca(2+) handling proteins; modifications of action potential shape and duration; magnitudes and relaxation rates of [Ca(2+)]i transients; changes in intracellular and transmembrane Ca(2+) fluxes; and [Na(+)]i fluxes and dynamics. The model elucidates complex interactions of ionic currents upon activation of ?1-adrenoceptors at different stimulation frequencies, which ultimately lead to a relatively modest increase in action potential duration and significant increase in [Ca(2+)]i transients. In particular, the model includes two subpopulations of the L-type Ca(2+) channels, in caveolae and extracaveolae compartments, and their effects on the action potential and [Ca(2+)]i transients are investigated. The presented model can be used by researchers for the interpretation of experimental data and for the developments of mathematical models for other species or for pathological conditions.

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Sorcin ablation plus ?-adrenergic stimulation generate an arrhythmogenic substrate in mouse ventricular myocytes.

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Sorcin ablation plus β-adrenergic stimulation generate an arrhythmogenic substrate in mouse ventricular myocytes.

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