Therapies aimed at minimizing adverse remodeling in cardiovascular diseases on a molecular and cellular basis are urgently needed. Exosomes are nanosized lipid vesicles released from various cells that are able to mediate intercellular signaling and communication via their cargos. It has been increasingly demonstrated that exosomes from cardiomyocytes or stem/progenitor cells can promote cardiac repair and regeneration, but their mechanism has not been fully explained. Immune responses mediated by immune cells also play important and complicated roles in the progression of various cardiovascular diseases such as myocardial infarction and atherosclerosis. Exosomes derived from immune cells have shown pleiotropic effects on these pathological states, whether similar to or different from their parent cells. However, the underlying mechanism remains obscure. In this review, we first describe the biological characteristics and biogenesis of exosomes. Then we critically examine the emerging roles of exosomes in cardiovascular disease; the exosomes we focus on are derived from immune cells such as dendritic cells, macrophages, B cells, T cells, as well as neutrophils and mast cells. Among the cardiovascular diseases we discuss, we mainly focus on myocardial infarction and atherosclerosis. As active intercellular communicators, exosomes from immune cells may offer prospective diagnostic and therapeutic value in cardiovascular disease.

Backgroud: Myocardial infarction (MI) is one of the leading causes of global death. Dendritic cell-derived exosomes (DEXs) provide us with the possibility of improving cardiac function after MI but are limited by low retention times and short-lived therapeutic effects. In this study, we developed a novel drug delivery system incorporating alginate hydrogel that continuously releases DEXs and investigated the mechanisms underlying the action of DEXs in the improvement of cardiac function after MI. Results: We incorporated DEXs with alginate hydrogel (DEXs-Gel) and investigated controlled released ability and rheology, and found that DEXs-Gel release DEXs in a sustainable mammer and prolonged the retention time of DEXs but had no detrimental effects on the migration in vivo. Then DEXs-Gel was applicated in the MI model mice, we found that DEXs-Gel siginificantly enhanced the therapeutic effects of DEXs with regards to improving cardiac function after MI. Flow cytometry and immunofluorescence staining revealed that DEXs significantly upregulated the infiltration of Treg cells and M2 macrophages into the border zoom after MI, and DEXs activated regulatory T (Treg) cells and shifted macrophages to reparative M2 macrophages, both in vitro and in vivo. Conclusion: Our novel delivery method provides an innovative tool for enhancing the therapeutic effects of DEXs after MI. Further analysis revealed that DEXs exert effect by activating Treg cells and by modifying the polarization of macrophages. Graphic

Background: Both hyperglycaemia and dendritic cells (DCs) play causative roles in atherosclerosis. However, whether they interact in atherosclerosis remains uncertain. Therefore, we examined whether high glucose could regulate the expression of scavenger receptors responsible for oxidised low-density lipoprotein (oxLDL) uptake in DCs, a critical step in atherogenesis. In addition, we investigated the impact of glucose on DC maturation regarding changes in phenotype and cytokine secretion. Methods: Immature DCs were cultured with different concentrations of glucose (5.5 mmol/L, 15 mmol/L, 30 mmol/L) in the absence or presence of N-acetylcysteine (NAC), SB203580 or Bay11-7082 for 24 hours. We used 30 mmol/L mannitol as a high-osmolarity control treatment. The expression of the scavenger receptors SR-A, CD36 and LOX-1 was determined by real-time PCR and western blot analysis. Furthermore, DCs were incubated with DiI-labelled oxLDL. The DiI-oxLDL-incorporated fraction was investigated by flow cytometry analysis. The intracellular production of ROS in DCs was measured by dichlorodihydrofluorescein (DCF) fluorescence using confocal microscopy. Finally, flow cytometry analysis was used to investigate immunophenotypic protein expression (CD83 and CD86). Supernatant cytokine measurements were used for immune function assays. Results: The incubation of DCs with glucose enhanced, in a dose-dependent manner, the gene and protein expression of SR-A, CD36 and LOX-1. This effect was partially abolished by NAC, SB203580 and Bay11-7082. Incubation of DCs with mannitol (30 mmol/L) did not enhance these scavenger receptors’ expression. High glucose upregulated the production of ROS and expression of p38 MAPK in DCs. NAC partially reversed p38 MAPK upregulation. High glucose increased the oxLDL-uptake capacity of DCs. Blockage of the scavenger receptors SR-A and CD36 reduced oxLDL uptake, but blockage of LOX-1 did not. Furthermore, high-glucose (15 mmol/L or 30 mmol/L) treatment increased CD86 and CD83 in DCs. High glucose also increased IL-6 and IL-12 secretion and decreased IL-10 secretion. Conclusion: High glucose can increase the expression of the scavenger receptors SR-A, CD36 and LOX-1, which can increase the oxLDL-uptake capacity of DCs. High glucose induces a proinflammatory cytokine profile in human DCs, leading to DC maturation. These results support the hypothesis that atherosclerosis is aggravated by hyperglycaemia-induced DC activation and oxLDL uptake.

The transcription factor BTB and CNC homology 1 (Bach1) regulates genes involved in the oxidative stress response and cell‐cycle progression. We have recently shown that Bach1 impairs cell proliferation and promotes apoptosis in cultured endothelial cells (ECs), but the underlying mechanisms are largely uncharacterized. Here we demonstrate that Bach1 upregulation impaired the blood flow recovery from hindlimb ischemia and this effect was accompanied both by increases in reactive oxygen species (ROS) and cleaved caspase 3 levels and by declines in the expression of cyclin D1 in the injured tissues. We found that Bach1 overexpression induced mitochondrial ROS production and caspase 3‐dependent apoptosis and its depletion attenuated H₂O₂‐induced apoptosis in cultured human microvascular endothelial cells (HMVECs). Bach1‐induced apoptosis was largely abolished when the cells were cultured with N‐acetyl‐l‐cysteine (NAC), a ROS scavenger. Exogenous expression of Bach1 inhibited the cell proliferation and the expression of cyclin D1, induced an S‐phase arrest, and increased the expression of cyclin E2, which were partially blocked by NAC. Taken together, our results suggest that Bach1 suppresses cell proliferation and induces cell‐cycle arrest and apoptosis by increasing mitochondrial ROS production, suggesting that Bach1 may be a promising treatment target for the treatment of vascular diseases.

Background: Contemporary risk assessment in patients with coronary atherosclerotic disease (CAD) often relies on invasive angiography. However, we aimed to explore the potential of metabolomic biomarkers in reflecting residual risk in patients with CAD after moderate lipid‐lowering therapy. Methods and Results: We analyzed serum metabolomic profile among 2560 patients with newly diagnosed CAD undergoing moderate lipid‐lowering therapy, through nuclear magnetic resonance spectroscopy and quantified 175 metabolites, predominantly lipoproteins and their components. CAD severity was evaluated using Gensini score for plaque burden and circulating cardiac troponin T levels for plaque instability. The association of metabolites with CAD severity was examined using multivariate linear regression, and the underlying potential causality was explored using a 2‐sample Mendelian randomization approach. Two composite metabolomic indices were constructed to reflect CAD severity using least absolute shrinkage and selection operator linear regression, and their associations with risk of major adverse cardiac events during a median follow‐up of 3.8 years were evaluated using Cox models. Our investigation revealed that triglycerides and apolipoprotein B in low‐density lipoprotein particles displayed stronger associations with CAD severity compared with the clinically used low‐density lipoprotein cholesterol marker. In large high‐density lipoprotein, components like cholesterol, cholesterol esters, triglyceride, apolipoprotein A1/A2 showed inverse associations with CAD severity. Certain metabolites, including apolipoprotein B and dihydrothymine, showed a putative causal link with Gensini score. Notably, per standard deviation increase in Gensini score–based metabolomic index was associated with 14.8% higher major adverse cardiac event risk (hazard ratio, 1.148 [95% CI, 1.018–1.295]) independent of demographic factors, medication use, and disease status. Conclusions: Our findings highlight the potential of nuclear magnetic resonance–based metabolomics in identifying novel biomarkers of plaque burden and instability. Metabolites related to plaque burden may facilitate noninvasive assessment of CAD prognosis.