Abstract
Abstract 4134792: SIRTUIN5 Modulates Na + /Ca 2+ Handling Via Oxidative Stress Dependent Manner In Mouse Heart
Circulation (New York, N.Y.), Vol.150(Suppl_1)
11/12/2024
DOI: 10.1161/circ.150.suppl_1.4134792
Abstract
Abstract only Background: The cardiac Na + channel Na V 1.5 (encoded by SCN5A ) governs cardiac inward Na + current (I Na ) and the fast upstroke and plateau phases of the cardiac action potential. Mutations in Na V 1.5 can cause acquired or inherited arrhythmias and conduction diseases, including ~20% of cases of Brugada Syndrome (BrS). Changes in I Na can impact Ca 2+ handling and cardiac excitation-contraction coupling. We have previously shown that SIRT1-mediated deacetylation of Na V 1.5 increased I Na . Recently, potential mutations (including P114T) in SIRT5, another NAD + -dependent deACYLase in the Sirtuin family localized to mitochondria, were identified in small families with BrS. Hypothesis: Sirt5 dysfunction evokes arrhythmias via Na + and Ca 2+ mishandling in an oxidative stress-dependent manner in mouse hearts. Aims: To explore the potential role of SIRT5 in BrS using heterologous expression systems and homozygous P114T-Sirt5 knock-in (P114T-KI) mice. Methods: Protein expression and physical interactions were detected by immunoprecipitation and immunoblot. The effects of SIRT5 on Na + current was measured using patch clamp in HEK cells and mouse cardiac myocytes. Confocal microscopy was used to measure reactive oxygen species (ROS) and for Ca 2+ imaging. Results: Both WT and P114T-SIRT5 co-immunoprecipitate with Na V 1.5, but WT increased peak I Na in HEK cells while P114T did not (Fig A,B). Live-cell staining using DCFDA or mitoSOX showed that P114T-KI hearts had increased basal ROS and were more sensitive to oxidative stress induced by H 2 O 2 than WT littermates. P114T-KI hearts had increased Na + /Ca 2+ exchange protein 1 (NCX1) expression, and Langendorff-perfused hearts displayed abnormal Ca 2+ handling and arrhythmias (Fig C). Notably, treatment with the mitochondrial ROS scavenger mitotempo mitigated the aberrant Ca 2+ handling and arrhythmias. Conclusion: These findings suggest that the P114T-SIRT5 causes abnormal Na + and Ca 2+ handling and arrhythmias in a ROS-dependent manner, highlighting potential mechanisms underlying BrS. This finding may pave the way for the use of SIRT5 or its activators as novel anti-arrhythmic therapies in the future.
Details
- Title: Subtitle
- Abstract 4134792: SIRTUIN5 Modulates Na + /Ca 2+ Handling Via Oxidative Stress Dependent Manner In Mouse Heart
- Creators
- Hannah Choi - University of IowaBiyi Chen - University of IowaLong-Sheng Song - University of IowaDavid Lombard - University of MiamiJin-Young Yoon - University of IowaBarry London - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.150(Suppl_1)
- Publisher
- LIPPINCOTT WILLIAMS & WILKINS
- DOI
- 10.1161/circ.150.suppl_1.4134792
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Language
- English
- Date published
- 11/12/2024
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine; Biochemistry and Molecular Biology
- Record Identifier
- 9984749859902771
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