Download The 10 Most Read Articles Published in Circulation Research in 2015

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The 10 Most Read Articles Published in Circulation Research in 2015
Roberto Bolli, for the Editors
We are pleased to provide the list of the 10 most read original articles published in Circulation
Research in 2015. We realize that the number of citations is the most conventional parameter used
to gauge interest by the readership; however, providing this metric would require a few years, by
which time the articles may have lost their novelty and appeal. Consequently, as we have done in
the past, we have selected the articles on the basis of the number of Full Text/PDF downloads,
which we hope will offer a reasonable estimate of the level of interest among our readers.
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Our motivation in compiling this list is multifarious. By highlighting the most popular articles, we
wish to direct the attention of our readers to new information that may be of particular interest to
a large fraction of the community of cardiovascular scholars. In addition, a synopsis of the most
popular articles can be a useful indicator of burgeoning areas of research that are likely to dominate
the landscape for years to come. This “honor roll” is also meant to acknowledge the outstanding
work of the authors and their efforts in advancing the frontiers of cardiovascular science.
Furthermore, we believe that the articles highlighted below represent paradigms of scientific
excellence, particularly with respect to the three criteria that we value most at Circulation
Research: conceptual and/or mechanistic novelty, scientific impact, and methodological rigor.
Finally, we hope that this list will provide tangible evidence of the high (and always rising) level
of scientific excellence of the work published in Circulation Research.
It should be noted that 4 of these ten articles report studies of noncoding RNAs (Zhao et al, Yan
et al, Climent et al, and Yang et al). The high number of downloads of these studies and their
disproportionate representation in the top 10 papers are further evidence of the enormous level of
interest that noncoding RNA biology attracts in the cardiovascular research community. Other
areas of emphasis include exosomes, stem cell biology, gene editing, and the gut microbiome. As
outlined in our editorial manifesto,1 rapid advances in these fields may transform cardiovascular
medicine. We view them as an important focus of the journal, and we are proud of the fact that
Circulation Research has been at the forefront of the explosive growth of cutting edge research,
both at the basic and at the translational levels.
-Roberto Bolli
The following represent a selection of the most read Circulation Research articles published
between January 2015 and December 2015, presented in their order of publication. Articles were
selected based on the number of Full Text/PDF downloads, adjusted to compensate for differences
in the time interval since publication.
DOI: 10.1161/CIRCRESAHA.116.308583
1
From the January 2, 2015 issue:
MicroRNA miR145 Regulates TGFBR2 Expression and Matrix Synthesis in Vascular
Smooth Muscle Cells
Ning Zhao, Sara N. Koenig, Aaron J. Trask, Cho-Hao Lin, Chetan P. Hans, Vidu Garg, Brenda
Lilly
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Abstract
Rationale: MicroRNA miR145 has been implicated in vascular smooth muscle cell
differentiation, but its mechanisms of action and downstream targets have not been fully defined.
Objective: Here, we sought to explore and define the mechanisms of miR145 function in smooth
muscle cells.
Methods and Results: Using a combination of cell culture assays and in vivo mouse models to
modulate miR145, we characterized its downstream actions on smooth muscle phenotypes. Our
results show that the miR-143/145 gene cluster is induced in smooth muscle cells by coculture
with endothelial cells. Endothelial cell–induced expression of miR-143/145 is augmented by
Notch signaling and accordingly expression is reduced in Notch receptor–deficient cells. Screens
to identify miR145-regulated genes revealed that the transforming growth factor (TGF)-β pathway
has a significantly high number of putative target genes, and we show that TGFβ receptor II is a
direct target of miR145. Extracellular matrix genes that are regulated by TGFβ receptor II were
attenuated by miR145 overexpression, and miR145 mutant mice exhibit an increase in
extracellular matrix synthesis. Furthermore, activation of TGFβ signaling via angiotensin II
infusion revealed a pronounced fibrotic response in the absence of miR145.
Conclusions: These data demonstrate a specific role for miR145 in the regulation of matrix gene
expression in smooth muscle cells and suggest that miR145 acts to suppress TGFβ-dependent
extracellular matrix accumulation and fibrosis, while promoting TGFβ-induced smooth muscle
cell differentiation. Our findings offer evidence to explain how TGFβ signaling exhibits distinct
downstream actions via its regulation by a specific microRNA.2
From the February 27, 2015 issue:
Effects of DNA Damage in Smooth Muscle Cells in Atherosclerosis
Kelly Gray, Sheetal Kumar, Nichola Figg, James Harrison, Lauren Baker, John Mercer, Trevor
Littlewood, Martin Bennett
Abstract
Rationale: DNA damage and the DNA damage response have been identified in human
atherosclerosis, including in vascular smooth muscle cells (VSMCs). However, although doublestranded breaks (DSBs) are hypothesized to promote plaque progression and instability, in part,
by promoting cell senescence, apoptosis, and inflammation, the direct effects of DSBs in VSMCs
seen in atherogenesis are unknown.
Objective: To determine the presence and effect of endogenous levels of DSBs in VSMCs on
atherosclerosis.
Methods and Results: Human atherosclerotic plaque VSMCs showed increased expression of
multiple DNA damage response proteins in vitro and in vivo, particularly the MRE11/RAD50/
DOI: 10.1161/CIRCRESAHA.116.308583
2
NBS1 complex that senses DSB repair. Oxidative stress–induced DSBs were increased in plaque
VSMCs, but DSB repair was maintained. To determine the effect of DSBs on atherosclerosis, we
generated 2 novel transgenic mice lines expressing NBS1 or C-terminal deleted NBS1 only in
VSMCs, and crossed them with apolipoprotein E–/– mice. SM22α-NBS1/apolipoprotein E–/–
VSMCs showed enhanced DSB repair and decreased growth arrest and apoptosis, whereas
SM22α-(ΔC)NBS1/apolipoprotein E–/– VSMCs showed reduced DSB repair and increased growth
arrest and apoptosis. Accelerating or retarding DSB repair did not affect atherosclerosis extent or
composition. However, VSMC DNA damage reduced relative fibrous cap areas, whereas
accelerating DSB repair increased cap area and VSMC content.
Conclusions: Human atherosclerotic plaque VSMCs show increased DNA damage, including
DSBs and DNA damage response activation. VSMC DNA damage has minimal effects on
atherogenesis, but alters plaque phenotype inhibiting fibrous cap areas in advanced lesions.
Inhibiting DNA damage in atherosclerosis may be a novel target to promote plaque stability.3
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From the March 27, 2015 issue:
lncRNA-MIAT Regulates Microvascular Dysfunction by Functioning as a Competing
Endogenous RNA
Biao Yan, Jin Yao, Jing-Yu Liu, Xiu-Miao Li, Xiao-Qun Wang, Yu-Jie Li, Zhi-Fu Tao, Yu-Chen
Song, Qi Chen, Qin Jiang
Abstract
Rationale: Pathological angiogenesis is a critical component of diseases, such as ocular disorders,
cancers, and atherosclerosis. It is usually caused by the abnormal activity of biological processes,
such as cell proliferation, cell motility, immune, or inflammation response. Long noncoding RNAs
(lncRNAs) have emerged as critical regulators of these biological processes. However, the role of
lncRNA in diabetes mellitus–induced microvascular dysfunction is largely unknown.
Objective: To elucidate whether lncRNA-myocardial infarction–associated transcript (MIAT) is
involved in diabetes mellitus–induced microvascular dysfunction.
Methods and Results: Using quantitative polymerase chain reaction, we demonstrated increased
expression of lncRNA-MIAT in diabetic retinas and endothelial cells cultured in high glucose
medium. Visual electrophysiology examination, TUNEL staining, retinal trypsin digestion,
vascular permeability assay, and in vitro studies revealed that MIAT knockdown obviously
ameliorated diabetes mellitus–induced retinal microvascular dysfunction in vivo, and inhibited
endothelial cell proliferation, migration, and tube formation in vitro. Bioinformatics analysis,
luciferase assay, RNA immunoprecipitation, and in vitro studies revealed that MIAT functioned
as a competing endogenous RNA, and formed a feedback loop with vascular endothelial growth
factor and miR-150-5p to regulate endothelial cell function.
Conclusions: This study highlights the involvement of lncRNA-MIAT in pathological
angiogenesis and facilitates the development of lncRNA-directed diagnostics and therapeutics
against neovascular diseases.4
DOI: 10.1161/CIRCRESAHA.116.308583
3
From the April 10, 2015 issue:
Vascular Smooth Muscle Cell Calcification Is Mediated by Regulated Exosome Secretion
Alexander N. Kapustin, Martijn L.L. Chatrou, Ignat Drozdov, Ying Zheng, Sean M. Davidson,
Daniel Soong, Malgorzata Furmanik, Pilar Sanchis, Rafael Torres Martin De Rosales, Daniel
Alvarez-Hernandez, Rukshana Shroff, Xiaoke Yin, Karin Muller, Jeremy N. Skepper, Manuel
Mayr, Chris P. Reutelingsperger, Adrian Chester, Sergio Bertazzo, Leon J. Schurgers, Catherine
M. Shanahan
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Abstract
Rationale: Matrix vesicles (MVs), secreted by vascular smooth muscle cells (VSMCs), form the
first nidus for mineralization and fetuin-A, a potent circulating inhibitor of calcification, is
specifically loaded into MVs. However, the processes of fetuin-A intracellular trafficking and MV
biogenesis are poorly understood.
Objective: The objective of this study is to investigate the regulation, and role, of MV biogenesis
in VSMC calcification.
Methods and Results: Alexa488-labeled fetuin-A was internalized by human VSMCs, trafficked
via the endosomal system, and exocytosed from multivesicular bodies via exosome release.
VSMC-derived exosomes were enriched with the tetraspanins CD9, CD63, and CD81, and their
release was regulated by sphingomyelin phosphodiesterase 3. Comparative proteomics showed
that VSMC-derived exosomes were compositionally similar to exosomes from other cell sources
but also shared components with osteoblast-derived MVs including calcium-binding and
extracellular matrix proteins. Elevated extracellular calcium was found to induce sphingomyelin
phosphodiesterase 3 expression and the secretion of calcifying exosomes from VSMCs in vitro,
and chemical inhibition of sphingomyelin phosphodiesterase 3 prevented VSMC calcification. In
vivo, multivesicular bodies containing exosomes were observed in vessels from chronic kidney
disease patients on dialysis, and CD63 was found to colocalize with calcification. Importantly,
factors such as tumor necrosis factor-α and platelet derived growth factor-BB were also found to
increase exosome production, leading to increased calcification of VSMCs in response to
calcifying conditions.
Conclusions: This study identifies MVs as exosomes and shows that factors that can increase
exosome release can promote vascular calcification in response to environmental calcium stress.
Modulation of the exosome release pathway may be as a novel therapeutic target for prevention.5
From the May 22, 2015 issue:
TGFβ Triggers miR-143/145 Transfer From Smooth Muscle Cells to Endothelial Cells,
Thereby Modulating Vessel Stabilization
Montserrat Climent, Manuela Quintavalle, Michele Miragoli, Ju Chen, Gianluigi Condorelli,
Leonardo Elia
Abstract
Rationale: The miR-143/145 cluster is highly expressed in smooth muscle cells (SMCs), where it
regulates phenotypic switch and vascular homeostasis. Whether it plays a role in neighboring
endothelial cells (ECs) is still unknown.
DOI: 10.1161/CIRCRESAHA.116.308583
4
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Objective: To determine whether SMCs control EC functions through passage of miR-143 and
miR-145.
Methods and Results: We used cocultures of SMCs and ECs under different conditions, as well
as intact vessels to assess the transfer of miR-143 and miR-145 from one cell type to another.
Imaging of cocultured cells transduced with fluorescent miRNAs suggested that miRNA transfer
involves membrane protrusions known as tunneling nanotubes. Furthermore, we show that
miRNA passage is modulated by the transforming growth factor (TGF) β pathway because both a
specific transforming growth factor-β (TGFβ) inhibitor (SB431542) and an shRNA against
TGFβRII suppressed the passage of miR-143/145 from SMCs to ECs. Moreover, miR-143 and
miR-145 modulated angiogenesis by reducing the proliferation index of ECs and their capacity to
form vessel-like structures when cultured on matrigel. We also identified hexokinase II (HKII)
and integrin β 8 (ITGβ8)—2 genes essential for the angiogenic potential of ECs—as targets of
miR-143 and miR-145, respectively. The inhibition of these genes modulated EC phenotype,
similarly to miR-143 and miR-145 overexpression in ECs. These findings were confirmed by ex
vivo and in vivo approaches, in which it was shown that TGFβ and vessel stress, respectively,
triggered miR-143/145 transfer from SMCs to ECs.
Conclusions: Our results demonstrate that miR-143 and miR-145 act as communication molecules
between SMCs and ECs to modulate the angiogenic and vessel stabilization properties of ECs.6
From the June 19, 2015 issue:
Embryonic Stem Cell-Derived Exosomes Promote Endogenous Repair Mechanisms and
Enhance Cardiac Function Following Myocardial Infarction
Mohsin Khan, Emily Nickoloff, Tatiana Abramova, Jennifer Johnson, Suresh Kumar Verma,
Prasanna Krishnamurthy, Alexander Roy Mackie, Erin Vaughan, Venkata Naga Srikanth
Garikipati, Cynthia Benedict, Veronica Ramirez, Erin Lambers, Aiko Ito, Erhe Gao, Sol Misener,
Timothy Luongo, John Elrod, Gangjian Qin, Steven R. Houser, Walter J. Koch, Raj Kishore
Abstract
Rationale: Embryonic stem cells (ESCs) hold great promise for cardiac regeneration but are
susceptible to various concerns. Recently, salutary effects of stem cells have been connected to
exosome secretion. ESCs have the ability to produce exosomes, however, their effect in the context
of the heart is unknown.
Objective: Determine the effect of ESC-derived exosome for the repair of ischemic myocardium
and whether c-kit+ cardiac progenitor cells (CPCs) function can be enhanced with ESC exosomes.
Methods and Results: This study demonstrates that mouse ESC-derived exosomes (mES Ex)
possess ability to augment function in infarcted hearts. mES Ex enhanced neovascularization,
cardiomyocyte survival, and reduced fibrosis post infarction consistent with resurgence of cardiac
proliferative response. Importantly, mES Ex augmented CPC survival, proliferation, and cardiac
commitment concurrent with increased c-kit+ CPCs in vivo 8 weeks after in vivo transfer along
with formation of bonafide new cardiomyocytes in the ischemic heart. miRNA array revealed
significant enrichment of miR290-295 cluster and particularly miR-294 in ESC exosomes. The
underlying basis for the beneficial effect of mES Ex was tied to delivery of ESC specific miR-294
to CPCs promoting increased survival, cell cycle progression, and proliferation.
DOI: 10.1161/CIRCRESAHA.116.308583
5
Conclusions: mES Ex provide a novel cell–free system that uses the immense regenerative power
of ES cells while avoiding the risks associated with direct ES or ES-derived cell transplantation
and risk of teratomas. ESC exosomes possess cardiac regeneration ability and modulate both
cardiomyocyte and CPC-based repair programs in the heart.7
From the July 3, 2015 issue:
Efficient Gene Disruption in Cultured Primary Human Endothelial Cells by CRISPR/Cas9
Parwiz Abrahimi, William G. Chang, Martin S. Kluger, Yibing Qyang, George Tellides, W. Mark
Saltzman, Jordan S. Pober
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Abstract
Rationale: The participation of endothelial cells (EC) in many physiological and pathological
processes is widely modeled using human EC cultures, but genetic manipulation of these
untransformed cells has been technically challenging. Clustered regularly interspaced short
palindromic repeats (CRISPR)/CRISPR-associated protein 9 nuclease (Cas9) technology offers a
promising new approach. However, mutagenized cultured cells require cloning to yield
homogeneous populations, and the limited replicative lifespan of well-differentiated human EC
presents a barrier for doing so.
Objective: To create a simple but highly efficient method using CRISPR/Cas9 to generate biallelic
gene disruption in untransformed human EC.
Methods and Results: To demonstrate proof-of-principle, we used CRISPR/Cas9 to disrupt the
gene for the class II transactivator. We used endothelial colony forming cell–derived EC and
lentiviral vectors to deliver CRISPR/Cas9 elements to ablate EC expression of class II major
histocompatibility complex molecules and with it, the capacity to activate allogeneic CD4+ T cells.
We show the observed loss-of-function arises from biallelic gene disruption in class II
transactivator that leaves other essential properties of the cells intact, including self-assembly into
blood vessels in vivo, and that the altered phenotype can be rescued by reintroduction of class II
transactivator expression.
Conclusions: CRISPR/Cas9-modified human EC provides a powerful platform for vascular
research and for regenerative medicine/tissue engineering.8
From the August 14, 2015 issue:
MicroRNA-34a Plays a Key Role in Cardiac Repair and Regeneration Following Myocardial
Infarction
Yanfei Yang, Hui-Wen Cheng, Yiling Qiu, David Dupee, Madyson Noonan, Yi-Dong Lin,
Sudeshna Fisch, Kazumasa Unno, Konstantina-Ioanna Sereti, Ronglih Liao
Abstract
Rationale: In response to injury, the rodent heart is capable of virtually full regeneration via
cardiomyocyte proliferation early in life. This regenerative capacity, however, is diminished as
early as 1 week postnatal and remains lost in adulthood. The mechanisms that dictate postinjury
cardiomyocyte proliferation early in life remain unclear.
DOI: 10.1161/CIRCRESAHA.116.308583
6
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Objective: To delineate the role of miR-34a, a regulator of age-associated physiology, in
regulating cardiac regeneration secondary to myocardial infarction (MI) in neonatal and adult
mouse hearts.
Methods and Results: Cardiac injury was induced in neonatal and adult hearts through
experimental MI via coronary ligation. Adult hearts demonstrated overt cardiac structural and
functional remodeling, whereas neonatal hearts maintained full regenerative capacity and
cardiomyocyte proliferation and recovered to normal levels within 1-week time. As early as 1
week postnatal, miR-34a expression was found to have increased and was maintained at high levels
throughout the lifespan. Intriguingly, 7 days after MI, miR-34a levels further increased in the adult
but not neonatal hearts. Delivery of a miR-34a mimic to neonatal hearts prohibited both
cardiomyocyte proliferation and subsequent cardiac recovery post MI. Conversely, locked nucleic
acid–based anti–miR-34a treatment diminished post-MI miR-34a upregulation in adult hearts and
significantly improved post-MI remodeling. In isolated cardiomyocytes, we found that miR-34a
directly regulated cell cycle activity and death via modulation of its targets, including Bcl2, Cyclin
D1, and Sirt1.
Conclusions: miR-34a is a critical regulator of cardiac repair and regeneration post MI in neonatal
hearts. Modulation of miR-34a may be harnessed for cardiac repair in adult myocardium.9
From the October 9, 2015 issue:
The Gut Microbiome Contributes to a Substantial Proportion of the Variation in Blood
Lipids
Jingyuan Fu, Marc Jan Bonder, María Carmen Cenit, Ettje F. Tigchelaar, Astrid Maatman,
Jackie A.M. Dekens, Eelke Brandsma, Joanna Marczynska, Floris Imhann, Rinse K. Weersma,
Lude Franke, Tiffany W. Poon, Ramnik J. Xavier, Dirk Gevers, Marten H. Hofker, Cisca
Wijmenga, Alexandra Zhernakova
Abstract
Rationale: Evidence suggests that the gut microbiome is involved in the development of
cardiovascular disease, with the host–microbe interaction regulating immune and metabolic
pathways. However, there was no firm evidence for associations between microbiota and
metabolic risk factors for cardiovascular disease from large-scale studies in humans. In particular,
there was no strong evidence for association between cardiovascular disease and aberrant blood
lipid levels.
Objectives: To identify intestinal bacteria taxa, whose proportions correlate with body mass index
and lipid levels, and to determine whether lipid variance can be explained by microbiota relative
to age, sex, and host genetics.
Methods and Results: We studied 893 subjects from the LifeLines-DEEP population cohort.
After correcting for age and sex, we identified 34 bacterial taxa associated with body mass index
and blood lipids; most are novel associations. Cross-validation analysis revealed that microbiota
explain 4.5% of the variance in body mass index, 6% in triglycerides, and 4% in high-density
lipoproteins, independent of age, sex, and genetic risk factors. A novel risk model, including the
gut microbiome explained ≤25.9% of high-density lipoprotein variance, significantly
outperforming the risk model without microbiome. Strikingly, the microbiome had little effect on
low-density lipoproteins or total cholesterol.
DOI: 10.1161/CIRCRESAHA.116.308583
7
Conclusions: Our studies suggest that the gut microbiome may play an important role in the
variation in body mass index and blood lipid levels, independent of age, sex, and host genetics.
Our findings support the potential of therapies altering the gut microbiome to control body mass,
triglycerides, and high-density lipoproteins.10
From the December 4, 2015 issue:
Sympathetic Reinnervation Is Required for Mammalian Cardiac
Ian A. White, Julie Gordon, Wayne Balkan, Joshua M. Hare
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Abstract
Rationale: Although mammalian cardiac regeneration can occur in the neonatal period, the factors
involved in this process remain to be established. Because tissue and limb regeneration require
concurrent reinnervation by the peripheral nervous system, we hypothesized that cardiac
regeneration also requires reinnervation.
Objective: To test the hypothesis that reinnervation is required for innate neonatal cardiac
regeneration.
Methods and Results: We crossed a Wnt1-Cre transgenic mouse with a double-tandem Tomato
reporter strain to identify neural crest-derived cell lineages including the peripheral autonomic
nerves in the heart. This approach facilitated the precise visualization of subepicardial autonomic
nerves in the ventricles using whole mount epifluorescence microscopy. After resection of the left
ventricular apex in 2-day-old neonatal mice, sympathetic nerve structures, which envelop the heart
under normal conditions, exhibited robust regrowth into the regenerating myocardium. Chemical
sympathectomy inhibited sympathetic regrowth and subsequent cardiac regeneration after apical
resection significantly (scar size as cross-sectional percentage of viable left ventricular
myocardium, n=9; 0.87%±1.4% versus n=6; 14.05±4.4%; P<0.01).
Conclusions: These findings demonstrate that the profound regenerative capacity of the neonatal
mammalian heart requires sympathetic innervation. As such, these data offer significant insights
into an underlying basis for inadequate adult regeneration after myocardial infarction, a situation
where nerve growth is hindered by age-related influences and scar tissue.11
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DOI: 10.1161/CIRCRESAHA.116.308583
9
The 10 Most Read Articles Published in Circulation Research in 2015
Roberto Bolli
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Circ Res. published online February 22, 2016;
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2016 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7330. Online ISSN: 1524-4571
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