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