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 K. Lieu, Javier E. López, J. Nilas Young, Ebenezer N. Yamoah, Fawaz Haj, Crystal M. Ripplinger, Bruce D. HammockNipavan Chiamvimonvat

Research output: Contribution to journalArticle

16 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Sirish, P., Li, N., Timofeyev, V., Zhang, X. D., Wang, L., Yang, J., Lee, K. S. S., Bettaieb, A., Ma, S. M., Lee, J. H., Su, D., Lau, V. C., Myers, R. E., Lieu, D. K., López, J. E., Young, J. N., Yamoah, E. N., Haj, F., Ripplinger, C. M., ... Chiamvimonvat, N. (2016). Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation. Circulation: Arrhythmia and Electrophysiology, 9(5), [e003721]. https://doi.org/10.1161/CIRCEP.115.003721