Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation

Abstract

Background Atrial fibrillation (AF) 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 (sEH) catalyzes the hydrolysis of anti-inflammatory epoxy fatty acids including epoxyeicosatrienoic acids (EETs) from arachidonic acid to the corresponding pro-inflammatory diols. Therefore, the goal of the study is to directly test the hypotheses that inhibition of the sEH enzyme can result in an increase in the levels of EETs leading to the attenuation of atrial structural and electrical remodeling and the prevention of AF. Methods and Results For the first time, we report findings that inhibition of sEH reduces inflammation, oxidative stress, atrial structural and electrical remodeling. Treatment with sEH inhibitor significantly reduces the activation of key inflammatory signaling molecules, including the transcription factor nuclear factor κ-light-chain-enhancer (NF-κB), mitogen-activated protein kinase (MAPK) and transforming growth factor-β (TGF-β). Conclusions This study provides insights into the underlying molecular mechanisms leading to AF 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 AF.

CYP2J2/EET reduces vulnerability to atrial fibrillation in chronic pressure overload mice

“…In addition to pro‐inflammatory response, NF‐κB also plays an important role in cardiac hypertrophy, which may increase AF occurrence. Moreover, overexpression of Smad‐7 was also demonstrated to restrain NF‐κB‐driven cardiac inflammation .…”

“…31 Pro-inflammatory cytokine levels were elevated with heart failure induced by TAC. 17 Therefore, to evaluate whether CYP2J2/EET counteracts the inflammatory response in AAC mice, we measured important pro-inflammatory cytokines and chemokines including TNF-α, IL-6 and MCP-1, and our data demonstrate the serum level of TNF-α, IL-6 and MCP-1 were significantly increased in mice with AAC ( Figure 5A). In contrast, treatment with AAV9-2J2 significantly decreased these cytokine levels.…”

Action Potential Shortening and Impairment of Cardiac Function by Ablation of Slc26a6

“…Histological and western blot analyses of cardiac tissue were performed as we have previously described 9 . Genotyping analyses of Slc26a6 − / − mice are presented in Supplemental Figure 1.…”

Probing the orientation of inhibitor and epoxy-eicosatrienoic acid binding in the active site of soluble epoxide hydrolase

“…Studies have shown that lcPUFA epoxides are anti-inflammatory, anti-hypertensive, organ protective and analgesic. [2-9] Therefore, stabilization of lcPUFA epoxides in vivo through sEH inhibition is generally beneficial to human health and certain diseases, like chronic obstructive pulmonary diseases (COPD),[10, 11] atrial fibrillation[12] and diabetic neuropathic pain. [13-15].…”