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Atrial fibrosis is an essential contributor to atrial fibrillation (AF). It remains unclear whether atrial endocardial endothelial cells (AEECs) that undergo endothelial-mesenchymal transition (EndMT) are among the sources of atrial fibroblasts. We studied human atria, TGF-[beta]-treated human AEECs, cardiac-specific TGF-[beta]-transgenic mice, and heart failure rabbits to identify the underlying mechanism of EndMT in atrial fibrosis. Using isolated AEECs, we found that miR-181b was induced in TGF-[beta]-treated AEECs, which decreased semaphorin 3A (Sema3A) and increased EndMT markers, and these effects could be reversed by a miR-181b antagomir. Experiments in which Sema3A was increased by a peptide or decreased by a siRNA in AEECs revealed a mechanistic link between Sema3A and LIM-kinase 1/phosphorylated cofilin (LIMK/p-cofilin) signaling and suggested that Sema3A is upstream of LIMK in regulating actin remodeling through p-cofilin. Administration of the miR181b antagomir or recombinant Sema3A to TGF-[beta]-transgenic mice evoked increased Sema3A, reduced EndMT markers, and significantly decreased atrial fibrosis and AF vulnerability. Our study provides a mechanistic link between the induction of EndMT by TGF-[beta] via miR-181b/Sema3A/LIMK/p-cofilin signaling to atrial fibrosis. Blocking miR-181b and increasing Sema3A are potential strategies for AF therapeutic intervention., Introduction Atrial fibrillation (AF) is the most common sustained arrhythmia and results in increased morbidity and mortality. Rhythm control in persistent long-term AF, which is characterized by severe atrial myocyte [...]

Atrial fibrillation (AF), characterized by structural remodeling involving atrial myocardial degradation and fibrosis, is linked with obesity and transforming growth factor beta 1 (TGF-β1). Aldehyde dehydrogenase 2 (ALDH2) deficiency, highly prevalent in East Asian people, is paradoxically associated with a lower AF risk. This study investigated the impact of ALDH2 deficiency on diet-induced obesity and AF vulnerability in mice, exploring potential compensatory upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme-oxygenase 1 (HO-1). Wild-type (WT) and ALDH2*2 knock-in (KI) mice were administered a high-fat diet (HFD) for 16 weeks. Despite heightened levels of reactive oxygen species (ROS) post HFD, the ALDH2*2 KI mice did not exhibit a greater propensity for AF compared to the WT controls. The ALDH2*2 KI mice showed equivalent myofibril degradation in cardiomyocytes compared to WT after chronic HFD consumption, indicating suppressed ALDH2 production in the WT mice. Atrial fibrosis did not proportionally increase with TGF-β1 expression in ALDH2*2 KI mice, suggesting compensatory upregulation of the Nrf2 and HO-1 pathway, attenuating fibrosis. In summary, ALDH2 deficiency did not heighten AF susceptibility in obesity, highlighting Nrf2/HO-1 pathway activation as an adaptive mechanism. Despite limitations, these findings reveal a complex molecular interplay, providing insights into the paradoxical AF–ALDH2 relationship in the setting of obesity. [ABSTRACT FROM AUTHOR]

Background: Sustained, chronic activation of β-adrenergic receptor (β-AR) signaling leads to cardiac arrhythmias, with exchange proteins directly activated by cAMP (Epac1 and Epac2) as key mediators. This study aimed to evaluate whether CD44, a transmembrane receptor mediating various cellular responses, participates in Epac-dependent arrhythmias. Methods: The heart tissue from CD44 knockout (CD44−/−) mice, cultured HL-1 myocytes and the tissue of human ventricle were used for western blot, co-immunoprecipitaiton and confocal studies. Line-scanning confocal imaging was used for the study of cellular Ca2+ sparks on myocytes. Optical mapping and intra-cardiac pacing were applied for arrhythmia studies on mice's hearts. Results: In mice, isoproterenol, a β-AR agonist, upregulated CD44 and Epac1 and increased the association between CD44 and Epac1. Isoproterenol upregulated the expression of phospho-CaMKII (p-CaMKII), phospho-ryanodine receptor (p-RyR), and phospho-phospholamban (p-PLN) in mice and cultured myocytes; these effects were attenuated in CD44−/− mice compared with wild-type controls. In vitro, isoproterenol, 8-CPT-cAMP (an Epac agonist), and osteopontin (a ligand of CD44) significantly upregulated the expression of p-CaMKII, p-RyR, and p-PLN; this effect was attenuated by CD44 small interfering RNA (siRNA). In myocytes, resting Ca2+ sparks were induced by isoproterenol and overexpressed CD44, which were prevented by inhibiting CD44. Ex vivo optical mapping and in vivo intra-cardiac pacing studies showed isoproterenol-induced triggered events and arrhythmias in ventricles were prevented in CD44−/− mice. The inducibility of ventricular arrhythmias (VAs) was attenuated in CD44−/− HF mice compared with wild-type HF controls. In patients, CD44 were upregulated, and the association between CD44 and Epac1 were increased in ventricles with reduced contractility. Conclusion: CD44 regulates β-AR- and Epac1-mediated Ca2+-handling abnormalities and VAs. Inhibition of CD44 is effective in reducing VAs in HF, which is potentially a novel therapeutic target for preventing the arrhythmias and sudden cardiac death in patients with diseased hearts. [ABSTRACT FROM AUTHOR]

Aim: Hyperphosphatemia is associated with adverse cardiovascular outcomes in both the general population and patients with end‐stage renal disease. We evaluated whether high inorganic phosphate (Pi) intake causes atrial remodeling and increased atrial fibrillation (AF) risk. Methods: The 5/6 nephrectomized chronic kidney disease (CKD) mice were fed a high‐Pi (2%) diet for 10 weeks. AF vulnerability was evaluated through transesophageal burst atrial pacing. Phosphoproteomic, Western blotting, and immunohistochemistry were used to evaluate the effects of high Pi in atrial fibroblasts, atrial myocytes, and HL‐1 myocytes. Results: CKD and sham mice fed a high‐Pi diet exhibited increased AF vulnerability, atrial fibrosis, and oxidative stress compared with mice fed a normal diet. Compared with normal (1 mM) Pi, high (2 mM) Pi significantly increased the activity of atrial fibroblasts and mitochondrial oxidative stress. Phosphoproteomic analysis revealed that compared with normal Pi, high Pi considerably increased the phosphorylation of intracellular proteins in atrial fibroblasts, including proteins related to NF‐κB signaling and STAT3. Inhibition of NF‐κB, STAT3, and Nox4 by small interfering RNA reduced the high‐Pi‐induced expression of collagen. In HL‐1 myocytes, the high Pi induced the degradation of myofibril proteins and hyperphosphorylation of RyR2, which was abolished by Nox4 and CaMKII inhibition. Switching back to a normal‐Pi diet improved the atrial abnormalities induced by high‐Pi diet. Conclusions: High‐Pi intake causes atrial structural and electrical remodeling and increases AF vulnerability, which is mediated through STAT3/NF‐κB signaling and oxidative stress. High dietary Pi intake can exert detrimental effects on atria and may increase AF risk. [ABSTRACT FROM AUTHOR]