resolvin-d1 and Atrial-Fibrillation

Atrial fibrillation (AF) is the most common type of cardiac rhythm disturbance. At the cellular level, excessive ROS generation during AF is associated with ER stress, which induces an inflammatory response by activating the unfolded protein response (UPR) pathway and the nuclear factor-kappa B (NF-kB) signaling pathway. Activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome has been linked to the pathogenesis of AF through NF-kB activation and inflammatory cytokine secretion. It has been shown that NLRP3 inflammasome activation by endoplasmic reticulum (ER) stress is dependent on NF-kB activation. The anti-inflammatory role of resolvin D1 (RvD1), a pro-resolving mediator derived from omega-3 fatty acids, has demonstrated that the NF-κB/NLRP3 inflammasome pathway in different tissues is attenuated after treatment with RvD1. However, the mechanism of the anti-inflammatory activity of RvD1 in AF has not been clarified. This review suggests that RvD1 may inhibit ER stress-induced NLRP3 inflammasome through suppressing NF-κB in cardiac tissue and, thus ameliorate AF.

Topics: Animals; Anti-Inflammatory Agents; Atrial Fibrillation; Docosahexaenoic Acids; Endoplasmic Reticulum Stress; Humans; Inflammasomes; Inflammation; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Reactive Oxygen Species; Signal Transduction

Inflammation plays a role in atrial fibrillation (AF), but classical anti-inflammatory molecules are ineffective. Recent evidence suggests that failure of inflammation-resolution causes persistent inflammatory signalling and that a novel drug-family called resolvins promotes inflammation-resolution. Right heart disease (RHD) is associated with AF; experimental RHD shows signs of atrial inflammatory-pathway activation. Here, we evaluated resolvin-therapy effects on atrial arrhythmogenic remodelling in experimental RHD.. Pulmonary hypertension and RHD were induced in rats with an intraperitoneal injection of 60 mg/kg monocrotaline (MCT). An intervention group received daily resolvin-D1 (RvD1), starting 1 day before MCT administration. Right atrial (RA) conduction and gene-expression were analysed respectively by optical mapping and qPCR/gene-microarray. RvD1 had no or minimal effects on MCT-induced pulmonary artery or right ventricular remodelling. Nevertheless, in vivo transoesophageal pacing induced atrial tachyarrhythmias in no CTRL rats vs. 100% MCT-only rats, and only 33% RvD1-treated MCT rats (P < 0.001 vs. MCT-only). Conduction velocity was significantly decreased by MCT, an effect prevented by RvD1. RHD caused RA dilation and fibrosis. RvD1 strongly attenuated RA fibrosis but had no effect on RA dilation. MCT increased RA expression of inflammation- and fibrosis-related gene-expression pathways on gene-microarray transcriptomic analysis, effects significantly attenuated by RvD1 (334 pathways enriched in MCT-rats vs. control; only 177 dysregulated by MCT with RvD1 treatment). MCT significantly increased RA content of type 1 (proinflammatory) CD68-positive M1 macrophages without affecting type 2 (anti-inflammatory) M2 macrophages. RvD1-treated MCT-rat RA showed significant reductions in proinflammatory M1 macrophages and increases in anti-inflammatory M2 macrophages vs. MCT-only. MCT caused statistically significant increases in protein-expression (western blot) of COL3A1, ASC, CASP1, CASP8, IL1β, TGFβ3, CXCL1, and CXCL2, and decreases in MMP2, vs. control. RvD1-treatment suppressed all these MCT-induced protein-expression changes.. The inflammation-resolution enhancing molecule RvD1 prevents AF-promoting RA remodelling, while suppressing inflammatory changes and fibrotic/electrical remodelling, in RHD. Resolvins show potential promise in combating atrial arrhythmogenic remodelling by suppressing ongoing inflammatory signalling.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Anti-Inflammatory Agents; Atrial Fibrillation; Atrial Remodeling; Disease Models, Animal; Docosahexaenoic Acids; Fibrosis; Heart Atria; Heart Rate; Hypertension, Pulmonary; Inflammation Mediators; Macrophages; Male; Phenotype; Rats, Wistar; Signal Transduction; Transcriptome; Ventricular Dysfunction, Right