Macrophage-driven exosomes regulate the progression of cardiovascular disease

Abstract

Exosomes, as vital mediators of intercellular communication, play a critical role in the progression of cardiovascular disease (CVD). Recently, macrophage-derived exosomes (Mφ-Exos) have garnered increasing attention because of their significant potential in early diagnosis, pathological processes, and therapeutic applications for CVD. Exosomes contain diverse nucleic acids (e.g., miRNAs, mRNAs, and long noncoding RNAs (lncRNAs)) and proteins, which serve as specific biomarkers that regulate various stages of CVD. For example, miRNAs encapsulated within exosomes (e.g., miR-21, miR-133a, and miR-155) are closely associated with atherosclerosis, myocardial infarction, coronary artery disease, and stroke, and changes in their abundance can serve as diagnostic and prognostic indicators. Additionally, the composition of Mφ-Exos, including miRNAs, lipids, and proteins, plays a significant role in the initiation, progression, and inflammation of CVD. Research on Mφ-Exos provides new directions for early diagnosis, mechanistic exploration, and novel therapeutic targets in CVD. However, challenges remain regarding exosome isolation and identification technologies. Future studies need to further explore the biological properties of exosomes and develop more efficient, economical, and straightforward isolation methods. This review summarizes the multifaceted regulatory roles of Mφ-Exos in CVD, encompassing key processes such as inflammation, angiogenesis, metabolism, and cell death. Research has shown that M1-Exos promote the progression and exacerbation of CVD through pro-inflammatory and pro-fibrotic mechanisms, while M2-Exos demonstrate significant therapeutic potential via anti-inflammatory, pro-angiogenic, and metabolic reprogramming pathways. These findings not only reveal the complex mechanisms of Mφ-Exos in CVD but also provide new perspectives and potential targets for early diagnosis and precision treatment of the disease.

Keywords: cardiovascular disease; exosomes; extracellular vesicles; inflamation; macrophage polarization.

FIGURE 1

Formation and Function of Exosomes. Extracellular vesicles form when the plasma membrane invaginates, creating endosomes that develop into MVB. The TGN provides components for MVB maturation. MVB either degrade in lysosomes or release vesicles through membrane fusion. Vesicles can also form from mitochondrial or nuclear membranes. Key proteins like ALIX and TSG101 help in vesicle formation and cargo sorting. ALIX ALG-2-interacting protein X, MVB Multivesicular bodie, TSG101 tumor susceptibility gene 101 protein, TGN Trans-Golgi Network.

FIGURE 2

The Role of Mφ-Exos in Cardiovascular Inflammation. M1 and M2 macrophages have distinct roles in cardiovascular diseases. M1 exosomes release proinflammatory factors like miR-155 and TNF-α, activating pathways such as Sirt1-AMPKα2 and NF-κB, which inhibit endothelial cell growth and worsen cardiovascular disease. In contrast, M2 exosomes reduce inflammation by downregulating TNF-α and IL-1β in M1 macrophages. M2 exosomes also contain miR-21-5p and miR-148a, which regulate macrophage polarization and inhibit the TLR4/NF-κB/NLRP3 pathway, promoting tissue repair. AMPKα2 protein kinase AMP activated catalytic subunit alpha 2, EV extracellular vesicle, Exos Exosomes, IL Interleukin, LPS lipopolysaccharide, NF-κB nuclear factor κB, NLRP3 NACHT, LRR, PYD domain-containing protein 3, PAK2 p21 (RAC1)-activated kinase 2, PD-1 programmed cell death protein 1, RAC1 Rac family small GTPase 1, Sirt1 Sirtuin 1, TLR4 Toll-like receptor 4, TNF-α tumor necrosis factor-alpha.

FIGURE 3

The role of Mφ-Exos in cardiovascular angiogenesis. In MI, M1 exosomes release miR-155 and MALAT1, reducing endothelial cell angiogenesis and worsening heart dysfunction. M1 exosomes also contribute to cardiovascular disease via miR-503 and miR-185-3p, which inhibit endothelial cell growth and promote atherosclerosis. miR-222 from M1 exosomes causes arterial restenosis. In contrast, M2 exosomes release miR-132-3p and miR-221-3p, enhancing endothelial cell growth and angiogenesis, improving heart function. AMPK/Sirt1 Adenosine 5‘-monophosphate (AMP)-activated protein kinase/Sirtuin 1, CDKN1B/C cyclin-dependent kinase inhibitor 1B/C, EV Extracellular vesicle, Exos exsomes, Grb10 Growth factor receptor binding protein-10, HG High glucose, IGF1R Insulin-like growth factor 1 receptors, MALAT1 Metastasis Associated Lung Adenocarcinoma Transcript 1, MI Myocardial infarction, Smad7 Small mother against decapentaplegic-7, THBS1 Thrombospondin-1.

FIGURE 4

The Role of Mφ-Exos in Vascular Calcification and Myocardial Fibrosis. In HG conditions, Mφ exosomes contain miR-17-5p, which inhibits calcification in diabetic atherosclerotic plaques. They also carry GRP, reducing calcification in cardiovascular and joint tissues via anti-inflammatory effects. M1 exosomes promote calcific aortic valve disease through tsRNA-5006c-regulated autophagy. Meanwhile, M2-sEVs drive cardiac fibroblast proliferation and migration via CircUbe3a, contributing to myocardial fibrosis after acute myocardial infarction. AVIC Aortic valve interstitial cell, GRP Gla-rich protein; HG high glucose, Tβ4 Thymosin β4, sEVs small extracellular vesicles.

FIGURE 5

The role of Mφ-Exos in cardiovascular lipid metabolism Mφ exosomes significantly impact metabolic disorders. M1 exosomes contain miR-185-3p, which raises blood lipid levels and endothelial adhesion, while CD5L protein in these exosomes promotes atherosclerosis by regulating lipid metabolism in vascular smooth muscle cells. Accumulation of UC or rosiglitazone boosts vesicle and Mφ exosome secretion. LDL buildup increases macrophage adhesion to damaged endothelial cells, forming foam cells, which release more exosomes than normal macrophages, further worsening cardiovascular disease. AS atherosclerosis, CD5L CD5-like molecule, Exosome Exos, LDL low-density lipoprotein, PPARγ, TF tissue factor, UC unesterified cholesterol.