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MiR-135 protects against atrial fibrillation by suppressing intracellular calcium-mediated NLRP3 inflammasome activation.

ABSTRACT: Atrial fibrillation (AF), one of the most common types of arrhythmias, is associated with high morbidity and mortality, seriously endangering human health. Inflammation is closely associated with AF development. Activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome in cardiomyocytes has been shown to promote AF progression. Here, we demonstrate the effect of miR-135 on NLRP3 inflammasome and study the cardioprotective role of miR-135 in AF. We observed that overexpression of miR-135 in mice reduced the AF incidence and duration, and inhibited both excessive activation of NLRP3 inflammasome and the increased intracellular calcium release during AF. However, the inhibitory effect of miR-135 on AF was partly abolished in the presence of a specific agonist of the calcium-sensing receptor (CaSR). We showed in the present study that miR-135 has a protective effect against AF by suppressing intracellular calcium-mediated NLRP3 inflammasome activation, suggesting the potential of miR-135 as a therapeutic agent in the treatment of AF.

SUBMITTER: Yu Y

PROVIDER: S-EPMC10409699 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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miR-135 protects against atrial fibrillation by suppressing intracellular calcium-mediated NLRP3 inflammasome activation.

Yu Yahan Y Fan Zheyu Z Han Yanna Y Sun Xi X Dong Chaorun C Liu Guanqun G Yin Xinda X Liu Linhe L Bai Yunlong Y Yang Baofeng B

Journal of cell communication and signaling 20230124 3

Atrial fibrillation (AF), one of the most common types of arrhythmias, is associated with high morbidity and mortality, seriously endangering human health. Inflammation is closely associated with AF development. Activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome in cardiomyocytes has been shown to promote AF progression. Here, we demonstrate the effect of miR-135 on NLRP3 inflammasome and study the cardioprotective role of miR-135 in AF. We observed that ove ...[more]

PMID: 36692633

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Project description:Rationale: Extracellular vesicles (EVs) from human explant-derived cells injected directly into the atria wall muscle at the time of open chest surgery reduce atrial fibrosis, atrial inflammation, and atrial fibrillation (AF) in a rat model of sterile pericarditis. Albeit a promising solution to prevent postoperative AF, the mechanism(s) underlying this effect are unknown and it is not clear if this benefit is dependent on EV dose. Methods: To determine the dose-efficacy relationship of EVs from human explant-derived cells in a rat model of sterile pericarditis. Increasing doses of EVs (106, 107, 108 or 109) or vehicle control were injected into the atria of middle-age male Sprague-Dawley rats at the time of talc application. A sham control group was included to demonstrate background inducibility. Three days after surgery, all rats underwent invasive electrophysiological testing prior to sacrifice. Results: Pericarditis increased the likelihood of inducing AF (p<0.05 vs. sham). All doses decreased the probability of inducing AF with maximal effects seen after treatment with the highest dose (109, p<0.05 vs. vehicle). Pericarditis increased atrial fibrosis while EV treatment limited the effect of pericarditis on atrial fibrosis with maximal effects seen after treatment with 108 or 109 EVs. Increasing EV dose was associated with progressive decreases in pro-inflammatory cytokine content, inflammatory cell infiltration, and oxidative stress. EVs decreased NLRP3 (NACHT, LRR, and PYD domains-containing protein-3) inflammasome activation though a direct effect on resident atrial fibroblasts and macrophages. This suppressive effect was exclusive to EVs produced by heart-derived cells as application of EVs from bone marrow or umbilical cords did not alter NLRP3 activity. Conclusions: Intramyocardial injection of incremental doses of EVs at the time of open chest surgery led to progressive reductions in atrial fibrosis and inflammatory markers. These effects combined to render atria resistant to the pro-arrhythmic effects of pericarditis which is mechanistically related to suppression of the NLRP3 inflammasome.

Dataset Information

MiR-135 protects against atrial fibrillation by suppressing intracellular calcium-mediated NLRP3 inflammasome activation.

Publications

miR-135 protects against atrial fibrillation by suppressing intracellular calcium-mediated NLRP3 inflammasome activation.

Similar Datasets

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