Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation

Padmini Sirish, Ning Li, Valeriy Timofeyev, Xiao Dong Zhang, Lianguo Wang, Jun Yang, Kin Sing Stephen Lee, Ahmed Bettaieb, Sin Mei Ma, Jeong Han Lee, Demetria Su, Victor C. Lau, Richard E. Myers, Deborah Lieu, Javier E Lopez, J Nilas Young, Ebenezer N. Yamoah, Fawaz Haj, Crystal M Ripplinger, Bruce D. HammockNipavan Chiamvimonvat

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background - Atrial fibrillation represents the most common arrhythmia leading to increased morbidity and mortality, yet, current treatment strategies have proven inadequate. Conventional treatment with antiarrhythmic drugs carries a high risk for proarrhythmias. The soluble epoxide hydrolase enzyme catalyzes the hydrolysis of anti-inflammatory epoxy fatty acids, including epoxyeicosatrienoic acids from arachidonic acid to the corresponding proinflammatory diols. Therefore, the goal of the study is to directly test the hypotheses that inhibition of the soluble epoxide hydrolase enzyme can result in an increase in the levels of epoxyeicosatrienoic acids, leading to the attenuation of atrial structural and electric remodeling and the prevention of atrial fibrillation. Methods and Results - For the first time, we report findings that inhibition of soluble epoxide hydrolase reduces inflammation, oxidative stress, atrial structural, and electric remodeling. Treatment with soluble epoxide hydrolase inhibitor significantly reduces the activation of key inflammatory signaling molecules, including the transcription factor nuclear factor κ-light-chain-enhancer, mitogen-activated protein kinase, and transforming growth factor-β. Conclusions - This study provides insights into the underlying molecular mechanisms leading to atrial fibrillation by inflammation and represents a paradigm shift from conventional antiarrhythmic drugs, which block downstream events to a novel upstream therapeutic target by counteracting the inflammatory processes in atrial fibrillation.

Original languageEnglish (US)
Article numbere003721
JournalCirculation: Arrhythmia and Electrophysiology
Volume9
Issue number5
DOIs
StatePublished - May 1 2016

Fingerprint

Epoxide Hydrolases
Atrial Fibrillation
Anti-Arrhythmia Agents
Inflammation
Acids
Transforming Growth Factors
Enzymes
Mitogen-Activated Protein Kinases
Arachidonic Acid
Cardiac Arrhythmias
Oxidative Stress
Hydrolysis
Anti-Inflammatory Agents
Transcription Factors
Fatty Acids
Morbidity
Light
Mortality
Therapeutics

Keywords

  • animal model
  • arrhythmia
  • atrial fibrillation
  • eicosanoids
  • inflammation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation. / Sirish, Padmini; Li, Ning; Timofeyev, Valeriy; Zhang, Xiao Dong; Wang, Lianguo; Yang, Jun; Lee, Kin Sing Stephen; Bettaieb, Ahmed; Ma, Sin Mei; Lee, Jeong Han; Su, Demetria; Lau, Victor C.; Myers, Richard E.; Lieu, Deborah; Lopez, Javier E; Young, J Nilas; Yamoah, Ebenezer N.; Haj, Fawaz; Ripplinger, Crystal M; Hammock, Bruce D.; Chiamvimonvat, Nipavan.

In: Circulation: Arrhythmia and Electrophysiology, Vol. 9, No. 5, e003721, 01.05.2016.

Research output: Contribution to journalArticle

Sirish, P, Li, N, Timofeyev, V, Zhang, XD, Wang, L, Yang, J, Lee, KSS, Bettaieb, A, Ma, SM, Lee, JH, Su, D, Lau, VC, Myers, RE, Lieu, D, Lopez, JE, Young, JN, Yamoah, EN, Haj, F, Ripplinger, CM, Hammock, BD & Chiamvimonvat, N 2016, 'Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation', Circulation: Arrhythmia and Electrophysiology, vol. 9, no. 5, e003721. https://doi.org/10.1161/CIRCEP.115.003721
Sirish, Padmini ; Li, Ning ; Timofeyev, Valeriy ; Zhang, Xiao Dong ; Wang, Lianguo ; Yang, Jun ; Lee, Kin Sing Stephen ; Bettaieb, Ahmed ; Ma, Sin Mei ; Lee, Jeong Han ; Su, Demetria ; Lau, Victor C. ; Myers, Richard E. ; Lieu, Deborah ; Lopez, Javier E ; Young, J Nilas ; Yamoah, Ebenezer N. ; Haj, Fawaz ; Ripplinger, Crystal M ; Hammock, Bruce D. ; Chiamvimonvat, Nipavan. / Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation. In: Circulation: Arrhythmia and Electrophysiology. 2016 ; Vol. 9, No. 5.
@article{bd44bb9db29447d2942835a7cad196fd,
title = "Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation",
abstract = "Background - Atrial fibrillation represents the most common arrhythmia leading to increased morbidity and mortality, yet, current treatment strategies have proven inadequate. Conventional treatment with antiarrhythmic drugs carries a high risk for proarrhythmias. The soluble epoxide hydrolase enzyme catalyzes the hydrolysis of anti-inflammatory epoxy fatty acids, including epoxyeicosatrienoic acids from arachidonic acid to the corresponding proinflammatory diols. Therefore, the goal of the study is to directly test the hypotheses that inhibition of the soluble epoxide hydrolase enzyme can result in an increase in the levels of epoxyeicosatrienoic acids, leading to the attenuation of atrial structural and electric remodeling and the prevention of atrial fibrillation. Methods and Results - For the first time, we report findings that inhibition of soluble epoxide hydrolase reduces inflammation, oxidative stress, atrial structural, and electric remodeling. Treatment with soluble epoxide hydrolase inhibitor significantly reduces the activation of key inflammatory signaling molecules, including the transcription factor nuclear factor κ-light-chain-enhancer, mitogen-activated protein kinase, and transforming growth factor-β. Conclusions - This study provides insights into the underlying molecular mechanisms leading to atrial fibrillation by inflammation and represents a paradigm shift from conventional antiarrhythmic drugs, which block downstream events to a novel upstream therapeutic target by counteracting the inflammatory processes in atrial fibrillation.",
keywords = "animal model, arrhythmia, atrial fibrillation, eicosanoids, inflammation",
author = "Padmini Sirish and Ning Li and Valeriy Timofeyev and Zhang, {Xiao Dong} and Lianguo Wang and Jun Yang and Lee, {Kin Sing Stephen} and Ahmed Bettaieb and Ma, {Sin Mei} and Lee, {Jeong Han} and Demetria Su and Lau, {Victor C.} and Myers, {Richard E.} and Deborah Lieu and Lopez, {Javier E} and Young, {J Nilas} and Yamoah, {Ebenezer N.} and Fawaz Haj and Ripplinger, {Crystal M} and Hammock, {Bruce D.} and Nipavan Chiamvimonvat",
year = "2016",
month = "5",
day = "1",
doi = "10.1161/CIRCEP.115.003721",
language = "English (US)",
volume = "9",
journal = "Circulation: Arrhythmia and Electrophysiology",
issn = "1941-3149",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

TY - JOUR

T1 - Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation

AU - Sirish, Padmini

AU - Li, Ning

AU - Timofeyev, Valeriy

AU - Zhang, Xiao Dong

AU - Wang, Lianguo

AU - Yang, Jun

AU - Lee, Kin Sing Stephen

AU - Bettaieb, Ahmed

AU - Ma, Sin Mei

AU - Lee, Jeong Han

AU - Su, Demetria

AU - Lau, Victor C.

AU - Myers, Richard E.

AU - Lieu, Deborah

AU - Lopez, Javier E

AU - Young, J Nilas

AU - Yamoah, Ebenezer N.

AU - Haj, Fawaz

AU - Ripplinger, Crystal M

AU - Hammock, Bruce D.

AU - Chiamvimonvat, Nipavan

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Background - Atrial fibrillation represents the most common arrhythmia leading to increased morbidity and mortality, yet, current treatment strategies have proven inadequate. Conventional treatment with antiarrhythmic drugs carries a high risk for proarrhythmias. The soluble epoxide hydrolase enzyme catalyzes the hydrolysis of anti-inflammatory epoxy fatty acids, including epoxyeicosatrienoic acids from arachidonic acid to the corresponding proinflammatory diols. Therefore, the goal of the study is to directly test the hypotheses that inhibition of the soluble epoxide hydrolase enzyme can result in an increase in the levels of epoxyeicosatrienoic acids, leading to the attenuation of atrial structural and electric remodeling and the prevention of atrial fibrillation. Methods and Results - For the first time, we report findings that inhibition of soluble epoxide hydrolase reduces inflammation, oxidative stress, atrial structural, and electric remodeling. Treatment with soluble epoxide hydrolase inhibitor significantly reduces the activation of key inflammatory signaling molecules, including the transcription factor nuclear factor κ-light-chain-enhancer, mitogen-activated protein kinase, and transforming growth factor-β. Conclusions - This study provides insights into the underlying molecular mechanisms leading to atrial fibrillation by inflammation and represents a paradigm shift from conventional antiarrhythmic drugs, which block downstream events to a novel upstream therapeutic target by counteracting the inflammatory processes in atrial fibrillation.

AB - Background - Atrial fibrillation represents the most common arrhythmia leading to increased morbidity and mortality, yet, current treatment strategies have proven inadequate. Conventional treatment with antiarrhythmic drugs carries a high risk for proarrhythmias. The soluble epoxide hydrolase enzyme catalyzes the hydrolysis of anti-inflammatory epoxy fatty acids, including epoxyeicosatrienoic acids from arachidonic acid to the corresponding proinflammatory diols. Therefore, the goal of the study is to directly test the hypotheses that inhibition of the soluble epoxide hydrolase enzyme can result in an increase in the levels of epoxyeicosatrienoic acids, leading to the attenuation of atrial structural and electric remodeling and the prevention of atrial fibrillation. Methods and Results - For the first time, we report findings that inhibition of soluble epoxide hydrolase reduces inflammation, oxidative stress, atrial structural, and electric remodeling. Treatment with soluble epoxide hydrolase inhibitor significantly reduces the activation of key inflammatory signaling molecules, including the transcription factor nuclear factor κ-light-chain-enhancer, mitogen-activated protein kinase, and transforming growth factor-β. Conclusions - This study provides insights into the underlying molecular mechanisms leading to atrial fibrillation by inflammation and represents a paradigm shift from conventional antiarrhythmic drugs, which block downstream events to a novel upstream therapeutic target by counteracting the inflammatory processes in atrial fibrillation.

KW - animal model

KW - arrhythmia

KW - atrial fibrillation

KW - eicosanoids

KW - inflammation

UR - http://www.scopus.com/inward/record.url?scp=84969253549&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84969253549&partnerID=8YFLogxK

U2 - 10.1161/CIRCEP.115.003721

DO - 10.1161/CIRCEP.115.003721

M3 - Article

C2 - 27162031

AN - SCOPUS:84969253549

VL - 9

JO - Circulation: Arrhythmia and Electrophysiology

JF - Circulation: Arrhythmia and Electrophysiology

SN - 1941-3149

IS - 5

M1 - e003721

ER -