Search

A recent meta‐analysis among which four reports were conducted in Japan demonstrated that epicardial adipose tissue (EAT) is closely associated with an increased risk of atrial fibrillation (AF) recurrence after catheter ablation. We previously investigated the role of EAT in AF in humans. Left atrial (LA) appendage samples were obtained from AF patients during cardiovascular surgery. Histologically, the severity of fibrotic EAT remodeling was associated with LA myocardial fibrosis. Total collagen in the LA myocardium (i.e., LA myocardial fibrosis) was positively correlated with proinflammatory and profibrotic cytokines/chemokines, including interleukin‐6, monocyte chemoattractant protein‐1, and tumor necrosis factor‐α, in EAT. Human peri‐LA EAT and abdominal subcutaneous adipose tissue (SAT) were obtained by autopsy. EAT‐ or SAT‐derived conditioned medium was applied to the rat LA epicardial surface using an organo‐culture system. EAT‐conditioned medium induced atrial fibrosis in organo‐cultured rat atrium. The profibrotic effect of EAT was greater than that of SAT. The fibrotic area of the organo‐cultured rat atrium treated with EAT from patients with AF was greater than in patients without AF. Treatment with human recombinant angiopoietin‐like protein 2 (Angptl2) induced fibrosis in organo‐cultured rat atrium, which was suppressed by concomitant treatment with anti‐Angptl2 antibody. Finally, we attempted to detect fibrotic EAT remodeling on computed tomography (CT) images, which demonstrated that the percent change in EAT fat attenuation was positively correlated with EAT fibrosis. Based on these findings, we conclude that the percent change in EAT fat attenuation determined using CT non‐invasively detects EAT remodeling. Fibrotic epicardial adipose tissue remodeling.

TORC1 modulates proteosynthesis, nitrogen metabolism, stress responses, and autophagy. Here it is shown that the Sch9 branch of TORC1 signaling depends specifically on vacuolar membranes and that this specificity allows the cells to regulate selectively the outputs of divergent downstream pathways in response to oxidative stress.

Ego2 is characterized as a new subunit of Ego protein complex (the yeast Ragulaor counterpart) that is a scaffold of Gtr (the yeast Rag counterpart) and TORC1. Gtr1 and Gtr2 regulate the dynamic translocation of the Ego/Gtr/TORC1 supercomplex between the vacuolar limiting membrane and perivacuolar foci. This localization shift is closely associated with the TORC1 activity level.

Autophagy is an intracellular degradation process that delivers cytosolic material to lysosomes and vacuoles. To investigate the mechanisms that regulate autophagy, we performed a genome-wide screen using a yeast deletion-mutant collection, and found that Npr2 and Npr3 mutants were defective in autophagy. Their mammalian homologs, NPRL2 and NPRL3, were also involved in regulation of autophagy. Npr2-Npr3 function upstream of Gtr1-Gtr2, homologs of the mammalian RRAG GTPase complex, which is crucial for TORC1 regulation. Both npr2∆mutants and a GTP-bound Gtr1 mutant suppressed autophagy and increased Tor1 vacuole localization. Furthermore, Gtr2 binds to the TORC1 subunit Kog1. A GDP-bound Gtr1 mutant induced autophagy even under nutrient-rich conditions, and this effect was dependent on the direct binding of Gtr2 to Kog1. These results revealed that 2 molecular mechanisms, Npr2-Npr3-dependent GTP hydrolysis of Gtr1 and direct binding of Gtr2 to Kog1, are involved in TORC1 inactivation and autophagic induction.

Fibrotic remodeling of epicardial adipose tissue (EAT) is crucial for proinflammatory atrial myocardial fibrosis, which leads to atrial fibrillation (AF).