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Review
, 1852 (1), 1-11

Pathologic Function and Therapeutic Potential of Exosomes in Cardiovascular Disease

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Review

Pathologic Function and Therapeutic Potential of Exosomes in Cardiovascular Disease

Shaina Ailawadi et al. Biochim Biophys Acta.

Abstract

The heart is a very complex conglomeration of organized interactions between various different cell types that all aid in facilitating myocardial function through contractility, sufficient perfusion, and cell-to-cell reception. In order to make sure that all features of the heart work effectively, it is imperative to have a well-controlled communication system among the different types of cells. One of the most important ways that the heart regulates itself is by the use of extracellular vesicles, more specifically, exosomes. Exosomes are types of nano-vesicles, naturally released from living cells. They are believed to play a critical role in intercellular communication through the means of certain mechanisms including direct cell-to-cell contact, long-range signals as well as electrical and extracellular chemical molecules. Exosomes contain many unique features like surface proteins/receptors, lipids, mRNAs, microRNAs, transcription factors and other proteins. Recent studies indicate that the exosomal contents are highly regulated by various stress and disease conditions, in turn reflective of the parent cell status. At present, exosomes are well appreciated to be involved in the process of tumor and infection disease. However, the research on cardiac exosomes is just emerging. In this review, we summarize recent findings on the pathologic effects of exosomes on cardiac remodeling under stress and disease conditions, including cardiac hypertrophy, peripartum cardiomyopathy, diabetic cardiomyopathy and sepsis-induced cardiovascular dysfunction. In addition, the cardio-protective effects of stress-preconditioned exosomes and stem cell-derived exosomes are also summarized. Finally, we discuss how to epigenetically reprogram exosome contents in host cells which makes them beneficial for the heart.

Keywords: Cardiac remodeling; Cardiomyopathy; Exosomes; Stem cells; miRNAs.

Conflict of interest statement

Conflict of interest: The authors confirm that this article content has no conflict of interest.

Figures

Figure 1
Figure 1
The generation of microvesicles and exosomes. Microvesicles (MVs) are formed directly by outward budding or blebbing of the plasma membrane. Specific loading of membrane proteins, lipids and RNAs to the MVs in known to occur, but the exact molecular mechanism are largely unknown. Biogenesis of exosomes is initiated with inward budding of the cell membrane, with specific membrane proteins/receptors incorporated, to form early endosomes. Subsequently, the cargo is packaged into intraluminal vesicles (ILVs) upon second inward budding of the early endosome membrane, and then transformed into multivesicle bodies (MVBs). Four different mechanisms have been described to facilitate the cargo loading: 1) ESCRT machinery and associated proteins; 2) lipid rafts; 3) higher-ordered oligomerization; and 4) segregation into microdomains by ceramide. MVBs can then fuse with the lysosomal membrane and release ILVs for degradation. Alternatively, MVBs fuse with the plasma membrane and release ILVs into the extracellular space as exosomes, a process which is regulated by Rab27a, Rab11, Rab35, WNT5A, SNAREs, glycosphingolipids and flotillins, etc.
Figure 2
Figure 2
Under stress conditions, cardiac fibroblasts secret miR-21*-enriched exosomes, which are taken up by cardiomyocytes, leading to elevation of miR-21*. Consequently, the expression levels of SORBS2 and PDLIM5 are down-regulated in cardiomyocytes, resulting in cardiomyocyte hypertrophy.
Figure 3
Figure 3
In peripartum cardiomyopathy (PPCM) patients, Cathepsin D cleaves nursing hormone prolactin (PRL) to generate an antiangiogenic 16-kDa fragment, 16K PRL. 16K PRL stimulates both cardiac fibroblasts and endothelial cells to release miR-146a-enriched exosomes, which transport miR-146a to cardiomyocytes. The exosome-mediated elevation of miR-146a in cardiomyocytes can down-regulate the expression of Erbb4, Notch1, and Irak1, leading to slowed metabolism and impaired contractile function in cardiomyocytes. In addition, 16K PRL stimulates endothelial cells to activate NF-κB, which up-regulates miR-146a expression, leading to decreased levels of NRAS, IRAK1 and TRAF6 and consequently, inhibiting angiogenesis.
Figure 4
Figure 4
In type-2 diabetic rat hearts, miR-320 is up-regulated, whereas Hsp20 is down-regulated in cardiomyocytes. Accordingly, exosomes released from diabetic cardiomyocytes contain higher levels of miR-320, compared with those from healthy cardiomyocytes. The exosomal miR-320 is then transported to endothelial cells, resulting in decreased levels of IGF-1, Ets2 and Hsp20 and thereby, inhibiting angiogenesis in diabetic hearts. By contrast, healthy cardiomyocytes can secret miR-126- and Hsp20-enriched exosomes, which transfer miR-126 and Hsp20 to endothelial cells, leading to angiogenesis.
Figure 5
Figure 5
Sepsis can cause higher levels of lipopolysaccharide (LPS) and nitric oxide (NO) in the blood, which stimulate platelets to secret inflammatory exosomes. Such exosomes are enriched with NADPH, NOS, PGI, ICAM-1 and less miR-223, which activate ROS/RNS signaling pathways, increase NO production and activate Caspase-3 in both endothelial cells and cardiomyocytes, resulting in cell apoptosis and dysfunction and consequently, cardiomyopathy.
Figure 6
Figure 6
Multiple sources of stem cells, stress-preconditioned cells and gene-modified cells can yield cardio-protective exosomes. These protective exosomes, when injected into hearts, can interact with endothelial cells, cardiomyocytes, fibroblasts and other types of cells within hearts by endocytosis, receptor/ligand-mediated action, or membrane fusion, resulting in enhanced angiogenesis, reduced oxidative stress, decreased cell apoptosis/necrosis, and limited inflammatory response.

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