Abstract
Abstract P3131: SIRTUIN5 Modulates Na + /Ca 2+ Handling Through Oxidative Stress Dependent Mechanism In Mouse Heart
Circulation research, Vol.133(Suppl_1)
08/04/2023
DOI: 10.1161/res.133.suppl_1.P3131
Abstract
Abstract only Mutations in cardiac sodium channel Na V 1.5 (encoded by SCN5A) can cause inherited or acquired arrhythmias, including ~20% of cases of Brugada Syndrome (BrS) and inherited conduction disease. The peak Na V 1.5 current (I Na, Peak ) and the late current (I Na, Late ) govern the fast upstroke and plateau of the cardiac action potential, respectively. Ca 2+ ions impact excitation-contraction coupling, and imbalance in Na + /Ca 2+ homeostasis can cause electrical disturbance. BrS is characterized by a right bundle branch block pattern on EKG, arrhythmias, and sudden cardiac death. Recently, potential mutations in SIRT5, including P114T-SIRT5, were identified in small families with BrS. SIRT5 is a member of the Sirtuin family, acts as NAD + -dependent deACYLase.We explored the potential role of SIRT5 in BrS using heterologous expression systems and homozygous P114T-SIRT5 knock-in (P114T-KI) mice. SIRT5 co-immunoprecipitates with Na V 1.5 in HEK293 cells. Live-cell staining using DCFDA or mitoSOX showed that P114T-KI hearts had increased basal reactive oxygen species (ROS) and were more sensitive to oxidative stress induced by H 2 O 2 than wild-type littermates. P114T mice displayed Ca 2+ -mishandling as measured by Ca 2+ imaging in perfused hearts, increased I Na, Late , prolonged QTc, and arrhythmias. Notably, treatment with mitochondrial ROS scavenger mitotempo mitigated the aberrant Ca 2+ handling and arrhythmia in P114T mice.Together, these suggest that P114T-SIRT5 causes Na + /Ca 2+ mishandling-induced arrhythmias in ROS-dependent manner, highlighting potential mechanisms underlying BrS. They pave the way for using SIRT5 or its activators as novel anti-arrhythmic therapies.
Details
- Title: Subtitle
- Abstract P3131: SIRTUIN5 Modulates Na + /Ca 2+ Handling Through Oxidative Stress Dependent Mechanism In Mouse Heart
- Creators
- Jin-Young Yoon - University of IowaBiyi Chen - University of IowaSong Ling Sheng - The Univ of Iowa, Iowa City, IADavid B Lombard - University of MiamiBarry London - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Circulation research, Vol.133(Suppl_1)
- DOI
- 10.1161/res.133.suppl_1.P3131
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Language
- English
- Date published
- 08/04/2023
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984480136902771
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