Endothelial cells (ECs) and macrophages engage in tight and specific interactions that play critical roles in cardiovascular homeostasis and the pathogenesis of atherosclerosis. Extracellular vesicles (EVs) are circular membrane fragments released from the endosomal compartment as exosomes or shed from the surfaces of the membranes of most cell types. Increasing evidence indicates that EVs play a pivotal role in cell-to-cell communication. However, the contribution of EVs, as determine by oxidized low-density lipoprotein (ox-LDL)-exposed and/or Kruppel-like factor 2 (KLF2)-transduced ECs in the interaction between vascular ECs and monocytes/macrophages, which is a key event in atherosclerotic plaque development, has remained elusive. This study demonstrates the characteristic impact of EVs from ox-LDL-treated and/or KLF2-transduced ECs on the monocyte/macrophage phenotype in vitro and in vivo.Q-PCR showed that both the atherosclerosis inducer ox-LDL and atheroprotective factor KLF2 regulated inflammation-associated microRNA-155 (miR-155) expression in human umbilical vein endothelial cells (HUVECs). Moreover, coculture, immunofluorescence and flow cytometry revealed that miR-155 was enriched in ox-LDL-induced ECs-EVs and subsequently transferred to human monocytic THP1 cells, in which these vesicles enhance monocyte activation by shifting the monocytes/macrophages balance from anti-inflammatory M2 macrophages towards proinflammatory M1 macrophages; EVs from KLF2-expressing ECs suppressed monocyte activation by enhancing immunomodulatory responses and diminishing proinflammatory responses, which indicate the potent anti-inflammatory activities of these cells. Furthermore, oil red staining showed that atherosclerotic lesions were reduced in mice that received EVs from KLF2-transduced ECs with decreased proinflammatory M1 macrophages and increased anti-inflammatory M2 macrophages, and this effect is at least partly due to the decreased expression of inflammation-associated miR-155, confirming our in vitro findings. In summary, this study provides novel insights into the pathophysiological effects of altered EV secretion and/or microRNA content and their influence on modulating monocyte activation depending on the environment surrounding EVs-releasing ECs.

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Mild hypothermia is known to protect against ischemia and reperfusion (IR) injury. The exact mechanisms of the protection are not fully understood. Forkhead box O3 (FOXO3a) has been defined as a critical mediator in cellular processes, including oxidative stress, apoptosis, inflammation, cell death and DNA repair; however, the protection function in mild hypothermia has not been reported previously. The current study was designed to investigate the function of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/FOXO3a pathway in pretreatment with mild hypothermia during IR injury. Additionally, PI3K/AKT/FOXO3a signaling was inhibited using Ly294002 and the effect on the protective function of mild hypothermia pretreatment was evaluated. Furthermore, the apoptotic and inflammatory response induced by the IR injury was evaluated. Liver IR injury induced a significant increase in the level of apoptosis and inflammatory responses. However, pretreatment with mild hypothermia increased phospho (p)-AKT and p-FOXO3a following IR injury, and significantly reduced apoptosis and inflammatory cytokines release. However, inhibiting p-AKT and p-FOXO3a using Ly294002 suppressed the liver protection produced by mild hypothermia. In conclusion, these findings indicated that mild hypothermia pretreatment exhibited liver protective effects against IR injury associated with suppressing inflammatory cytokine release and apoptosis via the PI3K/AKT/FOXO3a pathway.

Background The association between ambient temperature and cardiovascular diseases has been well established, but evidence of temporal changes in the risk of acute aortic dissection (AAD) onset is lacking. Methods and Results We conducted an 8‐year time‐series study based on data from 2120 patients diagnosed with AAD at Tongji Hospital (Wuhan, China). Daily meteorological parameters were measured in the study area. Spearman's rank correlation analysis was applied to measure the associations between daily meteorological data and air pollution indicators. A distributed lag nonlinear model following quasi‐Poisson regression was used to express the nonlinear exposure‐response relationships and lag effects of daily mean temperature and temperature variability on the occurrence of AAD. Considering a 25‐day lag effect, lower or higher temperatures with reference to 25°C did not alter the onset risk of AAD. The lag effect of daily mean temperature on the incidence of AAD is statistically significant within 2 days, and the impact of daily mean temperature on the risk is most influential on the day. The exposure‐response curve between daily mean temperature and onset risks of AAD at lag 0 showed that the extremely cold temperature (2.5th percentile, 0.5°C) significantly increased the AAD risk for the total (relative risk, 1.733; 95% CI, 1.130–2.658) and type A dissection (relative risk, 3.951; 95% CI, 1.657–9.418). Temperature variability within 1 week did not affect the onset risks of AAD for the total. Conclusions We confirmed that extremely cold temperatures significantly increased the AAD risk, which could contribute to early prevention and timely diagnosis of the disease.