Distinct mechanisms mediate pacemaker dysfunction associated with catecholaminergic polymorphic ventricular tachycardia mutations: Insights from computational modeling
| Autor: | Ana Maria Gomez, Yael Yaniv, Joachim Behar, Limor Arbel-Ganon |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
IBMX SERCA Genotype Stimulation 030204 cardiovascular system & hematology Biology Catecholaminergic polymorphic ventricular tachycardia Models Biological Adenylyl cyclase 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Heart Conduction System medicine Cyclic AMP Animals Calsequestrin Genetic Predisposition to Disease Calcium Signaling Molecular Biology Alleles Mice Knockout Ryanodine receptor Sinoatrial node Ryanodine Receptor Calcium Release Channel medicine.disease Cyclic AMP-Dependent Protein Kinases Markov Chains Sarcoplasmic Reticulum 030104 developmental biology medicine.anatomical_structure chemistry Mutation Tachycardia Ventricular Calcium Signal transduction Cardiology and Cardiovascular Medicine Neuroscience Algorithms |
| Zdroj: | Journal of molecular and cellular cardiology. 143 |
| ISSN: | 1095-8584 |
| Popis: | Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced ventricular arrhythmia associated with rhythm disturbance and impaired sinoatrial node cell (SANC) automaticity (pauses). Mutations associated with dysfunction of Ca2+-related mechanisms have been shown to be present in CPVT. These dysfunctions include impaired Ca2+ release from the ryanodine receptor (i.e., RyR2R4496C mutation) or binding to calsequestrin 2 (CASQ2). In SANC, Ca2+ signaling directly and indirectly mediates pacemaker function. We address here the following research questions: (i) what coupled-clock mechanisms and pathways mediate pacemaker mutations associated with CPVT in basal and in response to β-adrenergic stimulation? (ii) Can different mechanisms lead to the same CPVT-related pacemaker pauses? (iii) Can the mutation-induced deteriorations in SANC function be reversed by drug intervention or gene manipulation? We used a numerical model of mice SANC that includes membrane and intracellular mechanisms and their interconnected signaling pathways. In the basal state of RyR2R4496C SANC, the model predicted that the Na+-Ca2+ exchanger current (INCX) and T-type Ca2+ current (ICaT) mediate between changes in Ca2+ signaling and SANC dysfunction. Under β-adrenergic stimulation, changes in cAMP-PKA signaling and the sodium currents (INa), in addition to INCX and ICaT, mediate between changes in Ca2+ signaling and SANC automaticity pauses. Under basal conditions in Casq2-/-, the same mechanisms drove changes in Ca2+ signaling and subsequent pacemaker dysfunction. However, SANC automaticity pauses in response to β-AR stimulation were mediated by ICaT and INa. Taken together, distinct mechanisms can lead to CPVT-associated SANC automaticity pauses. In addition, we predict that specifically increasing SANC cAMP-PKA activity by either a pharmacological agent (IBMX, a phosphodiesterase (PDE) inhibitor), gene manipulation (overexpression of adenylyl cyclase 1/8) or direct manipulation of the SERCA phosphorylation target through changes in gene expression, compensate for the impairment in SANC automaticity. These findings suggest new insights for understanding CPVT and its therapeutic approach. |
| Databáze: | OpenAIRE |
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