Ibrutinib-induced pulmonary angiotensin-converting enzyme activation promotes atrial fibrillation in rats.

The molecular mechanism of ibrutinib-induced atrial fibrillation (AF) remains unclear. We here demonstrate that treating rats with ibrutinib for 4 weeks resulted in the development of inducible AF, left atrial enlargement, atrial fibrosis, and downregulation of connexin expression, which were associated with C-terminal Src kinase (CSK) inhibition and Src activation. Ibrutinib upregulated angiotensin-converting enzyme (ACE) protein expression in human pulmonary microvascular endothelial cells (HPMECs) by inhibiting the PI3K-AKT pathway, subsequently increasing circulating angiotensin II (Ang II) levels. However, the expression of ACE and Ang II in the left atria was not affected. Importantly, we observed that perindopril significantly mitigated ibrutinib-induced left atrial remodeling and AF promotion by inhibiting the activation of the ACE and its downstream CSK-Src signaling pathway. These findings indicate that the Ibrutinib-induced activation of the ACE contributes to AF development and could serve as a novel target for potential prevention strategies.

Atrial myocyte-derived exosomal microRNA contributes to atrial fibrosis in atrial fibrillation.

BACKGROUND: Atrial fibrosis plays a critical role in the development of atrial fibrillation (AF). Exosomes are a promising cell-free therapeutic approach for the treatment of AF. The purposes of this study were to explore the mechanisms by which exosomes derived from atrial myocytes regulate atrial remodeling and to determine whether their manipulation facilitates the therapeutic modulation of potential fibrotic abnormalities during AF. METHODS: We isolated exosomes from atrial myocytes and patient serum, and microRNA (miRNA) sequencing was used to analyze exosomal miRNAs in exosomes derived from atrial myocytes and patient serum. mRNA sequencing and bioinformatics analyses corroborated the key genes that were direct targets of miR-210-3p. RESULTS: The miRNA sequencing analysis identified that miR-210-3p expression was significantly increased in exosomes from tachypacing atrial myocytes and serum from patients with AF. In vitro, the miR-210-3p inhibitor reversed tachypacing-induced proliferation and collagen synthesis in atrial fibroblasts. Accordingly, miR-210-3p knock out (KO) reduced the incidence of AF and ameliorated atrial fibrosis induced by Ang II. The mRNA sequencing analysis and dual-luciferase reporter assay showed that glycerol-3-phosphate dehydrogenase 1-like (GPD1L) is a potential target gene of miR-210-3p. The functional analysis suggested that GPD1L regulated atrial fibrosis via the PI3K/AKT signaling pathway. In addition, silencing GPD1L in atrial fibroblasts induced cell proliferation, and these effects were reversed by a PI3K inhibitor (LY294002). CONCLUSIONS: Atrial myocyte-derived exosomal miR-210-3p promoted cell proliferation and collagen synthesis by inhibiting GPD1L in atrial fibroblasts. Preventing pathological crosstalk between atrial myocytes and fibroblasts may be a novel target to ameliorate atrial fibrosis in patients with AF.

A novel therapeutic strategy for alleviating atrial remodeling by targeting exosomal miRNAs in atrial fibrillation.

Atrial fibrillation (AF) is one of the most frequent cardiac arrhythmias, and atrial remodeling is related to the progression of AF. Although several therapeutic approaches have been presented in recent years, the continuously increasing mortality rate suggests that more advanced strategies for treatment are urgently needed. Exosomes regulate pathological processes through intercellular communication mediated by microribonucleic acid (miRNA) in various cardiovascular diseases (CVDs). Exosomal miRNAs associated with signaling pathways have added more complexity to an already complex direct cell-to-cell interaction. Exosome delivery of miRNAs is involved in cardiac regeneration and cardiac protection. Recent studies have found that exosomes play a critical role in the diagnosis and treatment of cardiac fibrosis. By improving exosome stability and modifying surface epitopes, specific pharmaceutical agents can be supplied to improve tropism and targeting to cells and tissues in vivo. Exosomes harboring miRNAs may have clinical utility in cell-free therapeutic approaches and may serve as prognostic and diagnostic biomarkers for AF. Currently, limitations challenge pharmaceutic design, therapeutic utility and in vivo targeted delivery to patients. The aim of this article is to review the developmental features of AF associated with exosomal miRNAs and relate them to underlying mechanisms.

Akkermansia muciniphila prevents cold-related atrial fibrillation in rats by modulation of TMAO induced cardiac pyroptosis.

BACKGROUND: Cold exposure is one of the most important risk factors for atrial fibrillation (AF), and closely related to the poor prognosis of AF patients. However, the mechanisms underlying cold-related AF are poorly understood. METHODS: Various techniques including 16S rRNA gene sequencing, fecal microbiota transplantation, and electrophysiological examination were used to determine whether gut microbiota dysbiosis promotes cold-related AF. Metabonomics were performed to investigate changes in fecal trimethylamine (TMA) and plasma trimethylamine N-oxide (TMAO) during cold exposure. The detailed mechanism underlying cold-related AF were examined in vitro. Transgenic mice were constructed to explore the role of pyroptosis in cold-related AF. The human cohort was used to evaluate the correlation between A. muciniphila and cold-related AF. FINDINGS: We found that cold exposure caused elevated susceptibility to AF and reduced abundance of Akkermansia muciniphila (A. muciniphila) in rats. Intriguingly, oral supplementation of A. muciniphila ameliorated the pro-AF property induced by cold exposure. Mechanistically, cold exposure disrupted the A. muciniphila, by which elevated the level of trimethylamine N-oxide (TMAO) through modulation of the microbial enzymes involved in trimethylamine (TMA) synthesis. Correspondingly, progressively increased plasma TMAO levels were validated in human subjects during cold weather. Raised TMAO enhanced the infiltration of M1 macrophages in atria and increased the expression of Casp1-p20 and cleaved-GSDMD, ultimately causing atrial structural remodeling. Furthermore, the mice with conditional deletion of caspase1 exhibited resistance to cold-related AF. More importantly, a cross-sectional clinical study revealed that the reduction of A. muciniphila abundance was an independent risk factor for cold-related AF in human subjects. INTERPRETATION: Our findings revealed a novel causal role of aberrant gut microbiota and metabolites in pathogenesis of cold-related AF, which raises the possibility of selectively targeting microbiota and microbial metabolites as a potential therapeutic strategy for cold-related AF. FUNDING: This work was supported by grants from the State Key Program of National Natural Science Foundation of China (No.81830012), and National Natural Science Foundation of China (No.82070336, No.81974024), Youth Program of the National Natural Science Foundation of China (No.81900374, No.81900302), and Excellent Young Medical Talents supporting project in the First Affiliated Hospital of Harbin Medical University (No. HYD2020YQ0001).

Epididymal white adipose tissue promotes angiotensin II-induced cardiac fibrosis in an exosome-dependent manner.

Cardiac fibrosis is a process characterized by extracellular matrix accumulation leading to myocardial dysfunction. Angiotensin II (Ang II) has been shown to play an important role in the pathogenesis of cardiac fibrosis. However, the underlying mechanisms are not well established. Dysfunction of adipose tissue has been shown to promote remote organ injury, but its role in Ang II-induced cardiac remodeling is still unclear. In this study, we demonstrated that epididymal white adipose tissue (eWAT) promoted Ang II-induced cardiac fibrosis and subsequent cardiac dysfunction in an exosome-dependent manner. Both eWAT removal and administration of an inhibitor of exosome biogenesis strongly attenuated Ang II-induced abnormalities. Moreover, exosomes isolated from Ang II-stimulated adipocytes promoted cardiac fibroblasts (CFs) activity. A mechanistic study identified that the miR-23a-3p level was significantly increased in exosomes derived from Ang II-challenged adipocytes and serum exosomes from Ang II-infused mice. Importantly, tail vein injection of ago-miR-23a-3p caused cardiac fibrosis and dysfunction, while antago-miR-23a-3p inhibited Ang II-induced cardiac fibrosis. Bioinformatics analysis and further validation experiments revealed that RAP1 is a direct downstream target of miR-23a-3p, and overexpression of RAP1 reversed the profibrotic effect of miR-23a-3p. Taken together, these findings elucidated the role of eWAT in Ang II-induced myocardial fibrosis and indicated that adipocyte-derived exosomes mediate pathologic communication between dysfunctional adipose tissue and the heart by transporting miR-23a-3p into CFs, transforming fibroblasts into myofibroblasts and promoting excessive collagen deposition by targeting RAP1. Prevention of abnormal adipocyte exosome production, inhibition of miR-23a-3p biogenesis, and treatment with a miR-23a-3p antagonist are novel strategies for treating cardiac fibrosis.