JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 65, NO. 15, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jacc.2015.02.028

EDITORIAL COMMENT

Exosomes Decrease Infarct Size* Jennifer L. Hall, PHD

E

xosomes are transport vesicles released from

size is reduced from w48% to 25% with delivery of

cells

acid,

exosomes (3). The data further suggest that the exo-

ribonucleic acid (RNA), and protein (1). Exo-

somes evoked cardioprotection via a heat shock pro-

somes have captured our attention with the explosion

tein (HSP), known as HSP70, on the surface of the

of diagnostics to measure the molecular profiles in-

exosome that is bound to toll-like receptor 4 (TLR4)

side these vesicles with the purpose of detecting,

on recipient cells. The recipient cells were not

diagnosing, and treating disease.

identified.

that

contain

deoxyribonucleic

In addition to diagnostics, therapeutic delivery

HSP levels are elevated after a myocardial infarc-

with exosomes is a topic on the minds of many. After

tion or after an ischemic event. Vicencio et al. (3)

all,

experienced

show that HSP70 resides on the surface of the rat

transportation system that provides a safe haven for

exosomes

represent

a

proven,

and human exosomes where it binds to TLR4 on the

circulating small molecules with a built-in docking

plasma membrane of recipient cells, leading to car-

system (1). If one pushes diagnostics and delivery

dioprotection through extracellular signal-regulated

aside, the simple, elegant fact remains that exosomes

protein kinases 1 and 2 (ERK1/2) phosphorylation,

regulate basic daily functions, including blood coag-

p38 mitogen-activated protein kinase (p38MAPK)

ulation (2). Exosomes also orchestrate responses to

activation, and phosphorylation of a second HSP,

specific biological conditions, including ischemia.

HSP27. They demonstrated that blockade of HSP70

Exosomes do not always contain protective contents,

with a neutralizing antibody prevented the car-

nor do they always promote a protective response.

dioprotective effects and the ERK1/2 and p38MAPK

For example, exosomes are secreted by cancerous

phosphorylation.

cells that perpetuate the cancer by suppressing

Vicencio et al. (3) also evaluated the delivery of an

immune responses. Today, many scientists and cli-

exosome fraction to rats through the tail vein before

nicians are working to define the roles of exosomes in

occlusion of the left anterior descending (LAD) artery

the setting of disease.

and showed a significant reduction in infarct size. A limitation of this study design was the lack of 2

SEE PAGE 1525

The study by Vicencio et al. (3) in this issue of the Journal provides new evidence of a cardioprotective effect of exosomes. Specifically, these authors demonstrate compelling new data that delivering plasma exosome fractions to rats before an ischemic event is cardioprotective. In fact, infarct

controls: LAD occlusion alone and delivery of donor rat plasma lacking exosomes. Exosomes were delivered to a cohort of rats before LAD occlusion; these rats were then compared to a second group of rats that received an infusion of phosphate-buffered saline before the LAD occlusion (3). Including a control with no tail vein injection before LAD would have been helpful in the interpretation of the results (to determine if the injections were altering the response to the LAD occlusion).

*Editorials published in the Journal of the American College of Cardiology

Second, including a control where the authors

reflect the views of the authors and do not necessarily represent the

lowered the exosomes in the circulation would have

views of JACC or the American College of Cardiology. From the Lillehei Heart Institute, Department of Medicine and Integrative Biology and Physiology, University of Minnesota, Minneapolis,

been ideal and would have served as a much stronger control compared with the phosphate-buffered saline

Minnesota. Dr. Hall is a consultant for University of South Florida Health,

used in the study. Adding a donor fraction of exo-

Tampa, Florida.

somes from a healthy rat, as was done, essentially

1538

Hall

JACC VOL. 65, NO. 15, 2015 APRIL 21, 2015:1537–8

Protection With Exosomes

doubles the amount of exosomes circulating in the

(50

rat (since no exosomes were removed in the study

with integrins, selectins, and CD40 ligand (1). Both

to

1000

nm)

and

are

typically

measured

design). Thus the animals receiving phosphate-

microvesicles and exosomes carry messenger RNA,

buffered saline still have exosomes. Of note, the

micro RNA, noncoding RNAs, and proteins (1). Vicencio

Langendorff preparation used as a second series of

et al. (3) show the mean size of the particles in their

experiments in this study will also contain exosomes

Figure 1D and they report it is around 75 nm for rats and

that are released from cells in the heart that circulate

humans. However, in their Figure 1B (3), you can see

in the perfusate. Given the field is still relatively young

the particle counts in both rat and human rise above

at understanding the therapeutic effects of exosomes

the 120 nm particle size. Again, better standardization

and standardizing the “exosome fraction,” scientists

and characterization of the exosomes in this study may

in this field will need to push the boundaries in rigid

have been useful.

controls and standards for defining exosome fractions.

Finally, the exosomes isolated in this study were

State-of-the-art technology has allowed scientists

from healthy rats and humans. It is not clear if exo-

to define exosomes with greater precision since the

somes or microparticles isolated from non-healthy

advent of their discovery more than 30 years ago.

rats and humans would produce the same beneficial

Exosomes are considered to be 40 to 120 nm in

effects.

size (1). Markers used to define exosomes include

Overall, the study from Vicencio et al. (3) raises

tetraspanins (including TSPAN29 and TSPAN30),

many new important questions for the field while

endosomal sorting complexes required for trans-

providing evidence of cardioprotection from exo-

port (ESCRT) components, programmed cell death

somes in the setting of ischemia and reperfusion.

6-interacting protein (PDCD6IP), tumor susceptibility gene 101 (TSG101), flotillin, and milk fat globule-

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

epidermal growth factor (EGF) 8 protein (MFG-E8)

Jennifer L. Hall, Department of Medicine and Integrative

(1). Cluster of differentiation (CD) 81 and CD63 have

Biology and Physiology, Lillehei Heart Institute, Univer-

also been used consistently in the literature to mark

sity of Minnesota, Cancer and Cardiovascular Research

exosomes and were used in this study by Vicencio et al.

Building, 2231 6th Street SE, Minneapolis, Minne-

(3). Microvesicles have a much larger range in size

sota 55455. E-mail: [email protected].

REFERENCES 1. EL Andaloussi S, Mager I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 2013;12:347–57. 2. Del Conde I, Shrimpton CN, Thiagarajan P, Lopez JA. Tissue-factor bearing microvesicles arise

from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 2005;106:1604–11. 3. Vicencio JM, Yellon DM, Sivaraman V, et al. Plasma exosomes protect the myocardium from ischemia-reperfusion injury. J Am Coll Cardiol 2015;65:1525–36.

KEY WORDS cardioprotection, heat shock protein 70, ischemia reperfusion, microparticles, toll-like receptor 4