Cardiac MAO-A inhibition protects against catecholamine-induced ventricular arrhythmias via enhanced diastolic calcium control

Qian Shi; Hamza Malik; Rachel M Crawford; Jennifer Streeter; Jinxi Wang; Ran Huo; Jean C Shih; Biyi Chen; Duane Hall; E Dale Abel; Long-Sheng Song; Ethan J Anderson

doi:10.1093/cvr/cvae012

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Cardiac MAO-A inhibition protects against catecholamine-induced ventricular arrhythmias via enhanced diastolic calcium control

Journal article

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Cardiac MAO-A inhibition protects against catecholamine-induced ventricular arrhythmias via enhanced diastolic calcium control

Qian Shi, Hamza Malik, Rachel M Crawford, Jennifer Streeter, Jinxi Wang, Ran Huo, Jean C Shih, Biyi Chen, Duane Hall, E Dale Abel, …

Cardiovascular research, Vol.120(6), pp.596-611

04/2024

DOI: 10.1093/cvr/cvae012

PMCID: PMC11074799

PMID: 38198753

Appears in UI Libraries Support Open Access

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Abstract

A mechanistic link between depression and risk of arrhythmias could be attributed to altered catecholamine metabolism in the heart. Monoamine oxidase-A (MAO-A), a key enzyme involved in catecholamine metabolism and longstanding antidepressant target, is highly expressed in the myocardium. The present study aimed to elucidate the functional significance and underlying mechanisms of cardiac MAO-A in arrhythmogenesis. Analysis of TriNetX database revealed that depressed patients treated with MAO inhibitors had a lower risk of arrhythmias compared to those treated with selective serotonin reuptake inhibitors. This effect was phenocopied in mice with cardiomyocyte-specific MAO-A deficiency (cMAO-Adef), which showed a significant reduction in both incidence and duration of catecholamine stress-induced ventricular tachyarrhythmias (VT) compared to wildtype mice. Additionally, cMAO-Adef cardiomyocytes exhibited altered Ca2+ handling under catecholamine stimulation, with increased diastolic Ca2+ reuptake, reduced diastolic Ca2+ leak, and diminished systolic Ca2+ release. Mechanistically, cMAO-Adef hearts had reduced catecholamine levels under sympathetic stress, along with reduced levels of reactive oxygen species (ROS) and protein carbonylation, leading to decreased oxidation of Type II PKA and CaMKII. These changes potentiated phospholamban (PLB) phosphorylation thereby enhancing diastolic Ca2+ reuptake while reducing ryanodine receptor 2 (RyR2) phosphorylation to decrease diastolic Ca2+ leak. Consequently, cMAO-Adef hearts exhibited lower diastolic Ca2+ levels and fewer arrhythmogenic Ca2+ waves during sympathetic overstimulation. Cardiac MAO-A inhibition exerts an anti-arrhythmic effect by enhancing diastolic Ca2+ handling under catecholamine stress. This study implicates catecholamine metabolism in arrhythmogenesis and reveals that monoamine oxidase is linked to Ca2+ regulation in the heart. It further illustrates therapeutic potential of cardiac MAO-A inhibition as a dual-purpose drug target to simultaneously manage depression and lower arrhythmia risk in affected patients.

Monoamine oxidase

Ventricular arrhythmia

Calcium

Catecholamine

Oxidative damage

Calcium–calmodulin (CaM)-dependent protein kinase II (CaMKII)

Protein kinase A (PKA)

UIOWA OA Agreement

Details

Title: Subtitle: Cardiac MAO-A inhibition protects against catecholamine-induced ventricular arrhythmias via enhanced diastolic calcium control
Creators: Qian Shi - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA
Hamza Malik - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA
Rachel M Crawford - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA
Jennifer Streeter - University of Iowa
Jinxi Wang - University of Iowa
Ran Huo - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA
Jean C Shih - University of Southern California
Biyi Chen - University of Iowa
Duane Hall - University of Iowa
E Dale Abel - University of Iowa
Long-Sheng Song - University of Iowa
Ethan J Anderson - University of Iowa
Resource Type: Journal article
Publication Details: Cardiovascular research, Vol.120(6), pp.596-611
DOI: 10.1093/cvr/cvae012
PMID: 38198753
PMCID: PMC11074799
NLM abbreviation: Cardiovasc Res
eISSN: 1755-3245
Publisher: Oxford University Press
Grant note: DOI: 10.13039/100000050, name: National Heart, Lung and Blood Institute, award: R01 HL122863, R21 HL057006, R01 HL130346, R01 HL157741, R01 HL157781; DOI: 10.13039/100000968, name: American Heart Association, award: 20SFRN35200003, CDA935054; DOI: 10.13039/100000738, name: Department of Veterans Affairs, award: I01-BX002334
Language: English
Electronic publication date: 01/10/2024
Date published: 04/2024
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Health, Sport, and Human Physiology ; Internal Medicine
Record Identifier: 9984543187502771

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