Advances in the study of exosomes in cardiovascular diseases

Abstract

Background: Cardiovascular disease (CVD) has been the leading cause of death worldwide for many years. In recent years, exosomes have gained extensive attention in the cardiovascular system due to their excellent biocompatibility. Studies have extensively researched miRNAs in exosomes and found that they play critical roles in various physiological and pathological processes in the cardiovascular system. These processes include promoting or inhibiting inflammatory responses, promoting angiogenesis, participating in cell proliferation and migration, and promoting pathological progression such as fibrosis.

Aim of review: This systematic review examines the role of exosomes in various cardiovascular diseases such as atherosclerosis, myocardial infarction, ischemia-reperfusion injury, heart failure and cardiomyopathy. It also presents the latest treatment and prevention methods utilizing exosomes. The study aims to provide new insights and approaches for preventing and treating cardiovascular diseases by exploring the relationship between exosomes and these conditions. Furthermore, the review emphasizes the potential clinical use of exosomes as biomarkers for diagnosing cardiovascular diseases.

Key scientific concepts of review: Exosomes are nanoscale vesicles surrounded by lipid bilayers that are secreted by most cells in the body. They are heterogeneous, varying in size and composition, with a diameter typically ranging from 40 to 160 nm. Exosomes serve as a means of information communication between cells, carrying various biologically active substances, including lipids, proteins, and small RNAs such as miRNAs and lncRNAs. As a result, they participate in both physiological and pathological processes within the body.

Graphical abstract

Fig. 1

Effect of different cells and their derived exosomes on atherosclerosis development Macrophages: M2 macrophages can uptake BMDM-IL-4-Exos containing miR-99a, miR-378b, miR-146b, and MSC-Exos containing miR-let7, miR-21a-5p, to achieve anti-inflammatory effects and inhibit the development of atherosclerosis. Conversely, M1 macrophages exhibit pro-inflammatory and pro-atherosclerotic characteristics, releasing miR-186-5p, miR-21a-5p, and miR-21a-5p under ox-LDL and nicotine stimulation. M1 macrophages exert pro-inflammatory and atherogenic effects by releasing exosomes containing miR-186-5p, AP-1, miR-21-3p, and miR-146a, which are taken up by VSMCs and neutrophils. ADSC-Exos, rich in miR-34a, can inhibit KLF4 transcription factor expression, promoting M1 macrophage polarization. Vascular Smooth Muscle Cells (VSMCs): miR-21-3p targets PTEN, and miR-186-5p targets SHIP2. Together, they enhance the PI3K/Akt/mTOR signaling pathway, driving the development of atherosclerosis. AP-1 protein and endothelial cell-derived exosomal miR-501-5p target Smad3, promoting VSMC proliferation, differentiation, and atherosclerosis development. Endothelial Cells: Macrophage-derived exosomal miR-4532 targets SP1, activates the NF-κB signaling pathway, leading to endothelial dysfunction and promoting atherosclerosis. Endothelial cells release exosomes containing miR-505 and lncRNA MALAT1, which are taken up by neutrophils. ADSC-Exos, rich in SNHG9 and miR-27-3p, influence inflammation and cell apoptosis. P-Exos contain miR-223 and miR-25-3p, targeting the NF-κB signaling pathway. ECFC-Exos regulate autophagic response through miR-21-5p. Circulating exosome circ_0001785 inhibits miR-513a-5p, thereby suppressing cell apoptosis, proliferation, and migration. Neutrophils: miR-146a downregulates SOD, leading to increased ROS and enhanced oxidative stress. Additionally, miR-505 and lncRNA MALAT1 together promote NET formation, accelerating atherosclerosis development.

Fig. 2

The effects of different sources of exosomes on angiogenesis after myocardial infarction M1 macrophage-derived exosome miR-55 can target the Sirt1/AMPK-eNOS axis and RAC-PAK1/2 axis, thereby inhibiting angiogenesis and endothelial cell migration; IL-10 KO EPC-derived exosomes are highly enriched in integrins, which can activate the downstream NF-κB signaling pathway, exerting an inhibitory effect on angiogenesis; miR-21-5p, a cardiac mesenchymal cell population (CTs)-derived exosome, silences Cdip1, thereby inhibiting Caspase3-mediated endothelial cell apoptosis; lncRNA H19 expression is elevated in MSC-derived exosomes treated with atorvastatin, causing an increase in miR-675 and ICAM-1, the miR-939-5p was able to target and inhibit iNOS expression and promote NO expression, which in turn promoted angiogenesis. miR-126-3p was able to inhibit TSC1, which led to an increase in downstream HIF-1α expression and promoted the angiogenesis process. ADSC-Exos are enriched with miR-31, which can be taken up by endothelial cells to suppress the expression of F1H1, alleviating the inhibitory effect on HIF-1α. This promotes angiogenesis.

Fig. 3

Effects of exosomes from different sources on cardiac function in patients with heart failure Activating peroxisome proliferator-activated receptors can promote the release of adiponectin, accelerate the release of exosomes from mesenchymal stem cells, and improve cardiac function; IPC Exosomes from hucMSCs in treated rat serum improved cardiac function; hucMSC-derived exosomes miR-1246 inhibited EMT and promoted angiogenesis; ESC-derived exosomes were enriched in FGF2 protein, which promoted angiogenesis, improve heart function; Cardiomyocyte-derived exosomal miR-494-3p can target and inhibit PTEN, activate the phosphorylation of Erk, Smad2/3 and Akt, and promote the process of myocardial fibrosis; exosomal miR-214-3p in peripheral blood can Promote neuroinflammation, while let-7g-5p and let-7i-5p can slow down neuroinflammation; TSC-derived exosomal miR-200 content decreased, which increased the expression of Zeb1, which can reduce DOX-induced cardiotoxicity.