Endothelial-derived APT1-mediated macrophage-endothelial cell interactions participate in the development of atherosclerosis by regulating the Ras/MAPK signaling pathway

Acyl-protein thioesterase 1 (APT1) can affect H-Ras localization and function by promoting its depalmitoylation. However, relatively little attention has been paid to the effects of APT1 on H-Ras in the cardiovascular system. In this study, we revealed its roles in atherosclerosis development using oxidative low-density lipoprotein (ox-LDL)-induced endothelial dysfunction models and a Western diet-induced ApoE−/− mouse model. The results showed that APT1 expression was up-regulated, while that of miR-138-5p (miR-138) was down-regulated (p < 0.05) in this model. In the meantime, APT1 and H-Ras were translocated from the cytoplasm to the plasma membrane. Bioinformatic analysis and double fluorescence identified miR-138 as the upstream regulator of APT1. APT1 knockdown regulated H-Ras localization and expression, which subsequently affected the MAPK signaling pathway and the expression of its downstream factors. Further research indicated that human umbilical vein endothelial cells (HUVECs)-derived biogenic nanoparticles (BiNPs), hBPs secretion, and RNA expression of hBP-loaded APT1 were increased (p < 0.05) in the ox-LDL induced endothelial dysfunction model. Meanwhile, the HUVECs-derived APT1 could further affect macrophage function through hBP transportation. Altogether, this study demonstrated that the miR-138-APT1 axis may be partially responsible for atherosclerosis development by regulating the H-Ras-MAPK signaling pathway and hBP transportation. The results also shed novel insight on the underlying mechanisms of, and identify potential diagnostic and therapeutic targets for, atherosclerotic cardiovascular diseases in the future

Efficacy of Wenxin Keli Plus Amiodarone versus Amiodarone Monotherapy in Treating Recent-Onset Atrial Fibrillation

Background. Use of amiodarone (AMIO) in atrial fibrillation (AF) has significant side effects over prolonged periods. Wenxin Keli (WXKL), a Chinese herb extract, has been shown to be effective in atrial-selective inhibiting peak INa and hence beneficial in treating atrial arrhythmias, including atrial fibrillation. The aim of this randomized controlled trial was to evaluate potential effects of AMIO plus WXKL on conversion rate and time in patients with recent-onset AF. Methods. A total of 41 patients (71 ± 12 years, 44% male) with recent-onset (<48 h) AF eligible for conversion were randomized to receive either intravenous amiodarone (loading dose 5 mg/kg in 1 hour followed by 50 mg/h; n=21) or amiodarone with same dosage plus oral WXKL 18 g thrice daily (n=20) for 24 hours. Results. Conversion rate at 24 hours was of no difference between the two groups (75.0% vs. 81.0%, P=0.72); however, conversion time was markedly shorter in the AMIO + WXKL group compared to the AMIO group (291 ± 235 minutes vs. 725 ± 475 minutes, P=0.003). There were no serious adverse events during the study. Conclusion. Administration of amiodarone plus WXKL for recent-onset AF conversion was safe and effective, with faster sinus rhythm restoration compared with amiodarone alone