Publications by authors named "Saumya Das"

108 Publications

Gaining Efficiency in Clinical Trials With Cardiac Biomarkers: JACC Review Topic of the Week.

J Am Coll Cardiol 2021 Apr;77(15):1922-1933

WCG Clinical and WCG-ACI Clinical, Bala Cynwood, Pennsylvania, USA.

The momentum of cardiovascular drug development has slowed dramatically. Use of validated cardiac biomarkers in clinical trials could accelerate development of much-needed therapies, but biomarkers have been used less for cardiovascular drug development than in therapeutic areas such as oncology. Moreover, there are inconsistences in biomarker use in clinical trials, such as sample type, collection times, analytical methods, and storage for future research. With these needs in mind, participants in a Cardiac Safety Research Consortium Think Tank proposed the development of international guidance in this area, together with improved quality assurance and analytical methods, to determine what biomarkers can reliably show. Participants recommended the development of systematic methods for sample collection, and the archiving of samples in all cardiovascular clinical trials (including creation of a biobank or repository). The academic and regulatory communities also agreed to work together to ensure that published information is fully and clearly expressed.
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http://dx.doi.org/10.1016/j.jacc.2021.02.040DOI Listing
April 2021

Split Ring Resonator-Based Bandstop Filter for Improving Isolation in Compact MIMO Antenna.

Sensors (Basel) 2021 Mar 24;21(7). Epub 2021 Mar 24.

Department of Electronics and Communication Engineering, Sikkim Manipal Institute of Technology, Sikkim Manipal University, Sikkim 737136, India.

The ever-growing expectation for high data rates has led to the introduction of multiple-input multiple-output (MIMO) technologies to wireless connectivity. Such a system requires an MIMO antenna with high isolation. At the same time, the MIMO dimension should not be compromised for achieving high isolation. Thus, isolation techniques that do not allow an increase in dimension need to be fostered for MIMO antenna design. In this paper, a novel low-profile, miniaturized MIMO antenna with high isolation was developed considering a split ring resonator (SRR)-based bandstop filter as a decoupling network. The bandstop filter was designed with a unit cell split ring resonator structure and was deployed between two closely spaced monopole MIMO antenna elements to obtain isolation as high as 39.25 dB at 2.61 GHz. Two open-circuit stub lines were attached with the MIMO feeding network to achieve good impedance matching at resonance frequency. The proposed antenna exhibited a peak gain of 3.8 dBi and radiation efficiency of 84%. It had a low envelop correlation coefficient (ECC < 0.12), high diversity gain (DG > 9.95 dB), low mean effective gain ratio (MEG 1/MEG 2 < 0.05 dB), and low channel capacity loss (CCL < 0.042 bits/s/Hz) at resonance frequency. The overall antenna dimension was restricted to 44 mm ×22 mm (0.38 λ0×0.19 λ0) for its easy integration in compact wireless devices.
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http://dx.doi.org/10.3390/s21072256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037282PMC
March 2021

Angiotensin II-induced muscle atrophy via PPARγ suppression is mediated by miR-29b.

Mol Ther Nucleic Acids 2021 Mar 25;23:743-756. Epub 2020 Dec 25.

Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai 200444, China.

The activation of the renin-angiotensin system (RAS) induced by increased angiotensin II (AngII) levels has been implicated in muscle atrophy, which is involved in the pathogenesis of congestive heart failure. Although peroxisome proliferator-activated receptor gamma (PPARγ) activation can suppress RAS, the exact role of PPARγ in AngII-induced muscle atrophy is unclear. Here we identified PPARγ as a negative regulator of miR-29b, a microRNA that is able to promote multiple types of muscle atrophy. Suppression of miR-29b could prevent AngII-induced muscle atrophy both and . IGF1, PI3K(p85α), and Yin Yang 1 (YY1) were identified as target genes of miR-29b, and overexpression of these targets could rescue AngII-induced muscle atrophy. Importantly, inhibition of PPARγ was sufficient to induce muscle atrophy, while PPARγ overexpression could attenuate that. These data indicate that the PPARγ/miR-29b axis mediates AngII-induced muscle atrophy, and increasing PPARγ or inhibiting miR-29b represents a promising approach to counteract AngII-induced muscle atrophy.
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http://dx.doi.org/10.1016/j.omtn.2020.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868689PMC
March 2021

Characterization and oncolytic virus targeting of FAP-expressing tumor-associated pericytes in glioblastoma.

Acta Neuropathol Commun 2020 12 11;8(1):221. Epub 2020 Dec 11.

Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA, 02114, USA.

Cancer-associated fibroblasts (CAFs) are activated fibroblasts constituting the major stromal components in many types of cancer. CAFs contribute to hallmarks of cancer such as proliferation, invasion and immunosuppressive tumor microenvironment, and are associated with poor prognosis of patients with cancer. However, in glioblastoma (GBM), the most common and aggressive primary malignant brain tumor, our knowledge about CAFs or CAF-like stromal cells is limited. Here, using commonly accepted CAF markers, we characterized CAF-like cell populations in clinical glioma specimens and datasets along with mouse models of GBM. We found that tumor-associated pericytes marked by co-expression of fibroblast activation protein α (FAP) and PDGFRβ represent major stromal cell subsets in both human GBM and mouse GBM models, while a fraction of mesenchymal neoplastic cells also express FAP in patient tumors. Since oncolytic viruses can kill cancer cells and simultaneously modulate the tumor microenvironment by impacting non-neoplastic populations such as immune cells and tumor vasculature, we further investigated the ability of oncolytic viruses to target GBM-associated stromal cells. An oncolytic adenovirus, ICOVIR15, carrying ∆24-E1A and an RGD-fiber, infects and depletes FAP+ pericytes as well as GBM cells in murine GBM. Our study thus identifies FAP+/PDGFRβ+ pericytes as a major CAF-like stromal cell population in GBM, and highlights the unique property of this oncolytic adenovirus to target both GBM cells and GBM-associated stromal FAP+ cells.
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http://dx.doi.org/10.1186/s40478-020-01096-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730751PMC
December 2020

Inhibition of lncRNA MAAT Controls Multiple Types of Muscle Atrophy by cis- and trans-Regulatory Actions.

Mol Ther 2021 03 3;29(3):1102-1119. Epub 2020 Dec 3.

Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Sciences, Shanghai University, Shanghai 200444, China; School of Medicine, Shanghai University, Shanghai 200444, China. Electronic address:

Muscle atrophy is associated with negative outcomes in a variety of diseases. Identification of a common therapeutic target would address a significant unmet clinical need. Here, we identify a long non-coding RNA (lncRNA) (muscle-atrophy-associated transcript, lncMAAT) as a common regulator of skeletal muscle atrophy. lncMAAT is downregulated in multiple types of muscle-atrophy models both in vivo (denervation, Angiotensin II [AngII], fasting, immobilization, and aging-induced muscle atrophy) and in vitro (AngII, HO, and tumor necrosis factor alpha [TNF-α]-induced muscle atrophy). Gain- and loss-of-function analysis both in vitro and in vivo reveals that downregulation of lncMAAT is sufficient to induce muscle atrophy, while overexpression of lncMAAT can ameliorate multiple types of muscle atrophy. Mechanistically, lncMAAT negatively regulates the transcription of miR-29b through SOX6 by a trans-regulatory module and increases the expression of the neighboring gene Mbnl1 by a cis-regulatory module. Therefore, overexpression of lncMAAT may represent a promising therapy for muscle atrophy induced by different stimuli.
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http://dx.doi.org/10.1016/j.ymthe.2020.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934634PMC
March 2021

Editorial: MicroRNA Signaling.

Front Cell Dev Biol 2020 30;8:612425. Epub 2020 Oct 30.

Alessandrescu-Rusescu National Institute of Mother and Child Health, Fetal Medicine Excellence Research Center, Bucharest, Romania.

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http://dx.doi.org/10.3389/fcell.2020.612425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661383PMC
October 2020

Possible Susceptibility Genes for Intervention against Chemotherapy-Induced Cardiotoxicity.

Oxid Med Cell Longev 2020 13;2020:4894625. Epub 2020 Oct 13.

Key Laboratory of Chinese Internal Medicine of the Ministry of Education, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China.

Recent therapeutic advances have significantly improved the short- and long-term survival rates in patients with heart disease and cancer. Survival in cancer patients may, however, be accompanied by disadvantages, namely, increased rates of cardiovascular events. Chemotherapy-related cardiac dysfunction is an important side effect of anticancer therapy. While advances in cancer treatment have increased patient survival, treatments are associated with cardiovascular complications, including heart failure (HF), arrhythmias, cardiac ischemia, valve disease, pericarditis, and fibrosis of the pericardium and myocardium. The molecular mechanisms of cardiotoxicity caused by cancer treatment have not yet been elucidated, and they may be both varied and complex. By identifying the functional genetic variations responsible for this toxicity, we may be able to improve our understanding of the potential mechanisms and pathways of treatment, paving the way for the development of new therapies to target these toxicities. Data from studies on genetic defects and pharmacological interventions have suggested that many molecules, primarily those regulating oxidative stress, inflammation, autophagy, apoptosis, and metabolism, contribute to the pathogenesis of cardiotoxicity induced by cancer treatment. Here, we review the progress of genetic research in illuminating the molecular mechanisms of cancer treatment-mediated cardiotoxicity and provide insights for the research and development of new therapies to treat or even prevent cardiotoxicity in patients undergoing cancer treatment. The current evidence is not clear about the role of pharmacogenomic screening of susceptible genes. Further studies need to done in chemotherapy-induced cardiotoxicity.
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http://dx.doi.org/10.1155/2020/4894625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578723PMC
October 2020

Mir-30d Regulates Cardiac Remodeling by Intracellular and Paracrine Signaling.

Circ Res 2021 Jan 22;128(1):e1-e23. Epub 2020 Oct 22.

Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston (A.M.S., G.L., N.V., O.Z., A.Y., C.Y.X., R.S.R., PK., M.G.S., R.K., R.S., S.D.).

Rationale: Previous translational studies implicate plasma extracellular microRNA-30d (miR-30d) as a biomarker in left ventricular remodeling and clinical outcome in heart failure (HF) patients, although precise mechanisms remain obscure.

Objective: To investigate the mechanism of miR-30d-mediated cardioprotection in HF.

Methods And Results: In rat and mouse models of ischemic HF, we show that miR-30d gain of function (genetic, lentivirus, or agomiR-mediated) improves cardiac function, decreases myocardial fibrosis, and attenuates cardiomyocyte (CM) apoptosis. Genetic or locked nucleic acid-based knock-down of miR-30d expression potentiates pathological left ventricular remodeling, with increased dysfunction, fibrosis, and cardiomyocyte death. RNA sequencing of in vitro miR-30d gain and loss of function, together with bioinformatic prediction and experimental validation in cardiac myocytes and fibroblasts, were used to identify and validate direct targets of miR-30d. miR-30d expression is selectively enriched in cardiomyocytes, induced by hypoxic stress and is acutely protective, targeting MAP4K4 (mitogen-associate protein kinase 4) to ameliorate apoptosis. Moreover, miR-30d is secreted primarily in extracellular vesicles by cardiomyocytes and inhibits fibroblast proliferation and activation by directly targeting integrin α5 in the acute phase via paracrine signaling to cardiac fibroblasts. In the chronic phase of ischemic remodeling, lower expression of miR-30d in the heart and plasma extracellular vesicles is associated with adverse remodeling in rodent models and human subjects and is linked to whole-blood expression of genes implicated in fibrosis and inflammation, consistent with observations in model systems.

Conclusions: These findings provide the mechanistic underpinning for the cardioprotective association of miR-30d in human HF. More broadly, our findings support an emerging paradigm involving intercellular communication of extracellular vesicle-contained miRNAs (microRNAs) to transregulate distinct signaling pathways across cell types. Functionally validated RNA biomarkers and their signaling networks may warrant further investigation as novel therapeutic targets in HF.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790887PMC
January 2021

Noncoding RNAs in Cardiovascular Disease: Current Knowledge, Tools and Technologies for Investigation, and Future Directions: A Scientific Statement From the American Heart Association.

Circ Genom Precis Med 2020 08 29;13(4):e000062. Epub 2020 Jun 29.

Background: The discovery that much of the non-protein-coding genome is transcribed and plays a diverse functional role in fundamental cellular processes has led to an explosion in the development of tools and technologies to investigate the role of these noncoding RNAs in cardiovascular health. Furthermore, identifying noncoding RNAs for targeted therapeutics to treat cardiovascular disease is an emerging area of research. The purpose of this statement is to review existing literature, offer guidance on tools and technologies currently available to study noncoding RNAs, and identify areas of unmet need.

Methods: The writing group used systematic literature reviews (including MEDLINE, Web of Science through 2018), expert opinion/statements, analyses of databases and computational tools/algorithms, and review of current clinical trials to provide a broad consensus on the current state of the art in noncoding RNA in cardiovascular disease.

Results: Significant progress has been made since the initial studies focusing on the role of miRNAs (microRNAs) in cardiovascular development and disease. Notably, recent progress on understanding the role of novel types of noncoding small RNAs such as snoRNAs (small nucleolar RNAs), tRNA (transfer RNA) fragments, and Y-RNAs in cellular processes has revealed a noncanonical function for many of these molecules. Similarly, the identification of long noncoding RNAs that appear to play an important role in cardiovascular disease processes, coupled with the development of tools to characterize their interacting partners, has led to significant mechanistic insight. Finally, recent work has characterized the unique role of extracellular RNAs in mediating intercellular communication and their potential role as biomarkers.

Conclusions: The rapid expansion of tools and pipelines for isolating, measuring, and annotating these entities suggests that caution in interpreting results is warranted until these methodologies are rigorously validated. Most investigators have focused on investigating the functional role of single RNA entities, but studies suggest complex interaction between different RNA molecules. The use of network approaches and advanced computational tools to understand the interaction of different noncoding RNA species to mediate a particular phenotype may be required to fully comprehend the function of noncoding RNAs in mediating disease phenotypes.
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http://dx.doi.org/10.1161/HCG.0000000000000062DOI Listing
August 2020

Profiling Extracellular Long RNA Transcriptome in Human Plasma and Extracellular Vesicles for Biomarker Discovery.

iScience 2020 Jun 18;23(6):101182. Epub 2020 May 18.

Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Simches 3(rd) Floor, Boston, MA 02114, USA. Electronic address:

The recent discovery of extracellular RNAs in blood, including RNAs in extracellular vesicles (EVs), combined with low-input RNA-sequencing advances have enabled scientists to investigate their role in human disease. To date, most studies have been focusing on small RNAs, and methodologies to optimize long RNAs measurement are lacking. We used plasma RNA to assess the performance of six long RNA sequencing methods, at two different sites, and we report their differences in reads (%) mapped to the genome/transcriptome, number of genes detected, long RNA transcript diversity, and reproducibility. Using the best performing method, we further compare the profile of long RNAs in the EV- and no-EV-enriched RNA plasma compartments. These results provide insights on the performance and reproducibility of commercially available kits in assessing the landscape of long RNAs in human plasma and different extracellular RNA carriers that may be exploited for biomarker discovery.
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http://dx.doi.org/10.1016/j.isci.2020.101182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283149PMC
June 2020

CITED4 Protects Against Adverse Remodeling in Response to Physiological and Pathological Stress.

Circ Res 2020 Aug 18;127(5):631-646. Epub 2020 May 18.

From the Corrigan Minehan Heart Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (C.L., C.P.R., A.Y., R.K., A.M.S., L.X.L., O.Z., K.D., C.P., R.S., F.D., P.K., S.D., A.R.).

Rationale: Cardiac CITED4 (CBP/p300-interacting transactivators with E [glutamic acid]/D [aspartic acid]-rich-carboxylterminal domain4) is induced by exercise and is sufficient to cause physiological hypertrophy and mitigate adverse ventricular remodeling after ischemic injury. However, the role of endogenous CITED4 in response to physiological or pathological stress is unknown.

Objective: To investigate the role of CITED4 in murine models of exercise and pressure overload.

Methods And Results: We generated cardiomyocyte-specific CITED4 knockout mice (C4KO) and subjected them to an intensive swim exercise protocol as well as transverse aortic constriction (TAC). Echocardiography, Western blotting, qPCR, immunohistochemistry, immunofluorescence, and transcriptional profiling for mRNA and miRNA (microRNA) expression were performed. Cellular crosstalk was investigated in vitro. CITED4 deletion in cardiomyocytes did not affect baseline cardiac size or function in young adult mice. C4KO mice developed modest cardiac dysfunction and dilation in response to exercise. After TAC, C4KOs developed severe heart failure with left ventricular dilation, impaired cardiomyocyte growth accompanied by reduced mTOR (mammalian target of rapamycin) activity and maladaptive cardiac remodeling with increased apoptosis, autophagy, and impaired mitochondrial signaling. Interstitial fibrosis was markedly increased in C4KO hearts after TAC. RNAseq revealed induction of a profibrotic miRNA network. miR30d was decreased in C4KO hearts after TAC and mediated crosstalk between cardiomyocytes and fibroblasts to modulate fibrosis. miR30d inhibition was sufficient to increase cardiac dysfunction and fibrosis after TAC.

Conclusions: CITED4 protects against pathological cardiac remodeling by regulating mTOR activity and a network of miRNAs mediating cardiomyocyte to fibroblast crosstalk. Our findings highlight the importance of CITED4 in response to both physiological and pathological stimuli.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725361PMC
August 2020

Y RNAs: Biogenesis, Function and Implications for the Cardiovascular System.

Adv Exp Med Biol 2020 ;1229:327-342

Cardiovascular Research Center of Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

In recent years, progress in the field of high-throughput sequencing technology and its application to a wide variety of biological specimens has greatly advanced the discovery and cataloging of a diverse set of non-coding RNAs (ncRNAs) that have been found to have unexpected biological functions. Y RNAs are an emerging class of highly conserved, small ncRNAs. There is a growing number of reports in the literature demonstrating that Y RNAs and their fragments are not just random degradation products but are themselves bioactive molecules. This review will outline what is currently known about Y RNA including biogenesis, structure and functional roles. In addition, we will provide an overview of studies reporting the presence and functions attributed to Y RNAs in the cardiovascular system.
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http://dx.doi.org/10.1007/978-981-15-1671-9_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363058PMC
July 2020

Extracellular vesicular microRNAs as potential biomarker for early detection of doxorubicin-induced cardiotoxicity.

J Vet Intern Med 2020 May 7;34(3):1260-1271. Epub 2020 Apr 7.

Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA.

Background: Long-term use of doxorubicin (DOX) is limited by cumulative dose-dependent cardiotoxicity.

Objectives: Identify plasma extracellular vesicle (EV)-associated microRNAs (miRNAs) as a biomarker for cardiotoxicity in dogs by correlating changes with cardiac troponin I (cTnI) concentrations and, echocardiographic and histologic findings.

Animals: Prospective study of 9 client-owned dogs diagnosed with sarcoma and receiving DOX single-agent chemotherapy (total of 5 DOX treatments). Dogs with clinically relevant metastatic disease, preexisting heart disease, or breeds predisposed to cardiomyopathy were excluded.

Methods: Serum concentration of cTnI was monitored before each treatment and 1 month after the treatment completion. Echocardiography was performed before treatments 1, 3, 5, and 1 month after completion. The EV-miRNA was isolated and sequenced before treatments 1 and 3, and 1 month after completion.

Results: Linear mixed model analysis for repeated measurements was used to evaluate the effect of DOX. The miR-107 (P = .03) and miR-146a (P = .02) were significantly downregulated whereas miR-502 (P = .02) was upregulated. Changes in miR-502 were significant before administration of the third chemotherapeutic dose. When stratifying miRNA expression for change in left ventricular ejection fraction, upregulation of miR-181d was noted (P = .01). Serum concentration of cTnI changed significantly but only 1 month after treatment completion, and concentrations correlated with left ventricular ejection fraction and left ventricular internal dimension in diastole.

Conclusion And Clinical Significance: Downregulation of miR-502 was detected before significant changes in cTnI concentrations or echocardiographic parameters. Further validation using a larger sample size will be required.
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http://dx.doi.org/10.1111/jvim.15762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255649PMC
May 2020

CRISPR/Cas9-Mediated miR-29b Editing as a Treatment of Different Types of Muscle Atrophy in Mice.

Mol Ther 2020 05 10;28(5):1359-1372. Epub 2020 Mar 10.

Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai 200444, China; School of Medicine, Shanghai University, Shanghai 200444, China. Electronic address:

Muscle atrophy is the loss of skeletal muscle mass and strength in response to diverse catabolic stimuli. At present, no effective treatments except exercise have been shown to reduce muscle atrophy clinically. Here, we report that CRISPR/Cas9-mediated genome editing through local injection into gastrocnemius muscles or tibialis anterior muscle efficiently targets the biogenesis processing sites in pre-miR-29b. In vivo, this CRISPR-based treatment prevented the muscle atrophy induced by angiotensin II (AngII), immobilization, and denervation via activation of the AKT-FOXO3A-mTOR signaling pathway and protected against AngII-induced myocyte apoptosis in mice, leading to significantly increased exercise capacity. Our work establishes CRISPR/Cas9-based gene targeting on miRNA as a potential durable therapy for the treatment of muscle atrophy and expands the strategies available interrogating miRNA function in vivo.
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http://dx.doi.org/10.1016/j.ymthe.2020.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210721PMC
May 2020

Neuronal activity triggers uptake of hematopoietic extracellular vesicles in vivo.

PLoS Biol 2020 03 16;18(3):e3000643. Epub 2020 Mar 16.

Institute of Neurology (Edinger Institute), University Hospital, Goethe University, Frankfurt am Main, Germany.

Communication with the hematopoietic system is a vital component of regulating brain function in health and disease. Traditionally, the major routes considered for this neuroimmune communication are by individual molecules such as cytokines carried by blood, by neural transmission, or, in more severe pathologies, by the entry of peripheral immune cells into the brain. In addition, functional mRNA from peripheral blood can be directly transferred to neurons via extracellular vesicles (EVs), but the parameters that determine their uptake are unknown. Using varied animal models that stimulate neuronal activity by peripheral inflammation, optogenetics, and selective proteasome inhibition of dopaminergic (DA) neurons, we show that the transfer of EVs from blood is triggered by neuronal activity in vivo. Importantly, this transfer occurs not only in pathological stimulation but also by neuronal activation caused by the physiological stimulus of novel object placement. This discovery suggests a continuous role of EVs under pathological conditions as well as during routine cognitive tasks in the healthy brain.
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http://dx.doi.org/10.1371/journal.pbio.3000643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075544PMC
March 2020

Circulating miRNAs and Risk of Sudden Death in Patients With Coronary Heart Disease.

JACC Clin Electrophysiol 2020 01 30;6(1):70-79. Epub 2019 Oct 30.

Cardiology Division and Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Objectives: This study evaluated whether plasma miRNAs were specifically associated with sudden cardiac and/or arrhythmic death (SCD) in a cohort of patients with coronary heart disease (CHD), most of whom were without primary prevention implantable cardioverter-defibrillators.

Background: Novel biomarkers for sudden death risk stratification are needed in patients with CHD to more precisely target preventive therapies, such as implantable cardioverter-defibrillators. miRNAs have been implicated in regulating inflammation and cardiac fibrosis in cells, and plasma miRNAs have been shown to predict cardiovascular death in patients with CHD.

Methods: We performed a nested case control study within a multicenter cohort of 5,956 patients with CHD followed prospectively for SCD. Plasma levels of 18 candidate miRNAs previously associated with cardiac remodeling were measured in 129 SCD cases and 258 control subjects matched on age, sex, race, and left ventricular ejection fraction.

Results: miR-150-5p, miR-29a-3p, and miR-30a-5p were associated with increased SCD risk (odds ratios and 95% confidence intervals: 2.03 [1.12 to 3.67]; p = 0.02; 1.93 [1.07 to 3.50]; p = 0.02; 0.55 [0.31 to 0.97]; p = 0.04, respectively, for third vs. first tertile miRNA level). Unfavorable levels of all 3 miRNAs was associated with a 4.8-fold increased SCD risk (1.59 to 14.51; p = 0.006). A bioinformatics-based approach predicted miR-150-5p, miR-29a-3p, and miR-30a-5p to be involved in apoptosis, fibrosis, and inflammation.

Conclusions: These findings suggest that plasma miRNAs may regulate pathways important for remodeling and may be useful in identifying patients with CHD at increased risk of SCD.
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http://dx.doi.org/10.1016/j.jacep.2019.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981228PMC
January 2020

Left ventricular wall thickness assessed by cardiac computed tomography and cardiac resynchronization therapy outcomes.

Europace 2020 03;22(3):401-411

Cardiology Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.

Aims: Up to 30% of selected heart failure patients do not benefit clinically from cardiac resynchronization therapy (CRT). Left ventricular (LV) wall thickness (WT) analysed using computed tomography (CT) has rarely been evaluated in response to CRT and mitral regurgitation (MR) improvement. We examined the association of LVWT and the ability to reverse LV remodelling and MR improvement after CRT.

Methods And Results: Fifty-four patients scheduled for CRT underwent pre-procedural CT. Reduced LVWT was defined as WT <6 mm and quantified as a percentage of total LV area. Endpoints were 6-month clinical and echocardiographic response to CRT [New York Heart Association (NYHA) class, LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), and LV end-systolic volume (LVESV)], MR improvement and 2-year major adverse cardiac events (MACE). Patients were divided into three groups according to the percentage of LVWT <6 mm area: ≤20%, 20-50%, and ≥50%. At 6 months, 75%, 71%, and 42% of the patients experienced NYHA improvement in the ≤20%, 20-50%, and ≥50% group, respectively. Additionally, ≤20% group presented higher LVEF, LVEDV, and LVESV positive response rate (86%, 59%, and 83%, respectively). Both 20-50% and ≥50% groups exhibited a lower LVEF, LVEDV, and LVESV positive response rate (52% and 42%; 47% and 45%; and 53% and 45%, respectively). Additionally, ≥25% of LVWT <6 mm inclusive of at least one papillary muscle insertion was the only predictor of lack of MR improvement. Lastly, ≥50% group experienced significantly lower 2-year MACE survival free probability.

Conclusion: WT evaluated using CT could help to stratify the response to CRT and predict MR improvement and outcomes.

Clinical Trial Registration: NCT01097733.
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http://dx.doi.org/10.1093/europace/euz322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058969PMC
March 2020

Comparison of Reproducibility, Accuracy, Sensitivity, and Specificity of miRNA Quantification Platforms.

Cell Rep 2019 12;29(12):4212-4222.e5

Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Diego, 9500 Gilman Drive, Mail Code 0695, La Jolla, CA 92093-0695, USA; Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA. Electronic address:

Given the increasing interest in their use as disease biomarkers, the establishment of reproducible, accurate, sensitive, and specific platforms for microRNA (miRNA) quantification in biofluids is of high priority. We compare four platforms for these characteristics: small RNA sequencing (RNA-seq), FirePlex, EdgeSeq, and nCounter. For a pool of synthetic miRNAs, coefficients of variation for technical replicates are lower for EdgeSeq (6.9%) and RNA-seq (8.2%) than for FirePlex (22.4%); nCounter replicates are not performed. Receiver operating characteristic analysis for distinguishing present versus absent miRNAs shows small RNA-seq (area under curve 0.99) is superior to EdgeSeq (0.97), nCounter (0.94), and FirePlex (0.81). Expected differences in expression of placenta-associated miRNAs in plasma from pregnant and non-pregnant women are observed with RNA-seq and EdgeSeq, but not FirePlex or nCounter. These results indicate that differences in performance among miRNA profiling platforms impact ability to detect biological differences among samples and thus their relative utility for research and clinical use.
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http://dx.doi.org/10.1016/j.celrep.2019.11.078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499898PMC
December 2019

Utility of Computed Tomography to Predict Ventricular Arrhythmias in Patients With Nonischemic Cardiomyopathy Receiving Cardiac Resynchronization Therapy.

Am J Cardiol 2020 02 19;125(4):607-612. Epub 2019 Nov 19.

Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

The residual risk of ventricular arrhythmia (VA) after cardiac resynchronization therapy (CRT) implantation in patients with nonischemic cardiomyopathy (NICM) remains difficult to evaluate. The impact of left ventricular (LV) wall thickness (WT) measured using computed tomography (CT) on the occurrence of VA after CRT implantation has never been investigated. In this pilot study, we examined the association of LV WT and the occurrence of VA in NICM patients receiving CRT. Thirty three patients with NICM scheduled for CRT underwent preprocedural CT. Reduced LV WT was defined as WT <6 mm and quantified as a percentage of total LV area. The end point was the occurrence of VA episode during 2-years follow-up after CRT implantation. During the 2-years follow-up, a total of 37 VA episodes occurred in 6 (18.2%) patients. Patients with VA exhibited significantly higher NT-pro BNP level before CRT implantation. Additionally, CT analysis showed that patients with VA had a higher percentage of total LV with reduced WT compared with those free from VA (49.5% vs 25.8%, respectively; p = 0.005). In multivariable analysis, the total percentage of LV area with WT <6 mm was the only predictor of VA (odds ratio 1.07 [1.00 to 1.14]; p = 0.047). Receiver-operator curves analysis for total percentage of LVWT <6 mm demonstrated that an optimal cut-off value of 40% differentiated patients at risk of VA. In conclusion, LVWT evaluated using cardiac CT is an independent predictor of VA in NICM patients implanted with CRT. Patients with a total percentage of LVWT <6 mm ≥40% are especially at high risk of VA after CRT implantation.
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http://dx.doi.org/10.1016/j.amjcard.2019.11.003DOI Listing
February 2020

Correction to: Exercise-induced circulating extracellular vesicles protect against cardiac ischemia-reperfusion injury.

Basic Res Cardiol 2019 Oct 8;114(6):44. Epub 2019 Oct 8.

Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, 333 Nan Chen Road, Shanghai, 200444, China.

The original version of this article unfortunately contained a mistake.
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http://dx.doi.org/10.1007/s00395-019-0751-0DOI Listing
October 2019

MiR-574-5p: A Circulating Marker of Thoracic Aortic Aneurysm.

Int J Mol Sci 2019 08 12;20(16). Epub 2019 Aug 12.

Cardiovascular Research Unit, Luxembourg Institute of Health, 1A-B rue Edison, L-1445 Strassen, Luxembourg.

Thoracic aortic aneurysm (TAA) can lead to fatal complications such as aortic dissection. Since aneurysm dimension poorly predicts dissection risk, microRNAs (miRNAs) may be useful to diagnose or risk stratify TAA patients. We aim to identify miRNAs associated with TAA pathogenesis and that are possibly able to improve TAA diagnosis. MiRNA microarray experiments of aortic media tissue samples from 19 TAA patients and 19 controls allowed identifying 232 differentially expressed miRNAs. Using interaction networks between these miRNAs and 690 genes associated with TAA, we identified miR-574-5p as a potential contributor of TAA pathogenesis. Interestingly, miR-574-5p was significantly down-regulated in the TAA tissue compared to the controls, but was up-regulated in serum samples from a separate group of 28 TAA patients compared to 20 controls ( < 0.001). MiR-574-5p serum levels discriminated TAA patients from controls with an area under the receiver operating characteristic curve of 0.87. In the mouse model, miR-574-5p was down-regulated in aortic tissue compared to wild-type ( < 0.05), and up-regulated in plasma extracellular vesicles from mice compared to wild-type mice ( < 0.05). Furthermore, in vascular smooth muscle cells, angiotensin II appears to induce miR-574-5p secretion in extracellular vesicles. In conclusion, miR-574-5p is associated with TAA pathogenesis and may help in diagnosing this disease.
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http://dx.doi.org/10.3390/ijms20163924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720007PMC
August 2019

Biomarker of Collagen Turnover (C-Terminal Telopeptide) and Prognosis in Patients With Non- ST -Elevation Acute Coronary Syndromes.

J Am Heart Assoc 2019 05;8(9):e011444

1 TIMI Study Group Division of Cardiovascular Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA.

Background Small studies have suggested an association between markers of collagen turnover and adverse outcomes in heart failure ( HF ). We examined C-terminal telopeptide (beta- CT x) and the risk of cardiovascular death or new or worsening HF in non- ST -elevation acute coronary syndrome. Methods and Results We measured baseline serum beta- CT x, NT -pro BNP (N-terminal pro-B-type natriuretic peptide), hsTnT (high-sensitivity cardiac troponin T) and hs CRP (high-sensitivity C-reactive protein) (Roche Diagnostics) in a nested biomarker analysis (n=4094) from a study of patients with non- ST -elevation acute coronary syndrome. The relationship between quartiles of beta- CT x and cardiovascular death or HF over a median follow-up time of 12 months was analyzed using adjusted Cox models. Higher beta- CT x levels identified a significantly higher risk of cardiovascular death/ HF (Q4 10.9% versus Q1 3.8%, Logrank P<0.001). After multivariable adjustment, beta- CT x in the top quartile (Q4) was associated with cardiovascular death/ HF (Q4 versus Q1: adjusted hazard ratio 2.22 [1.50-3.27]) and its components (Q4 versus Q1: cardiovascular death: adjusted hazard ratio 2.48 [1.46-4.21]; HF : adjusted hazard ratio 2.04 [1.26-3.30]). In an adjusted multimarker model including NT -pro BNP , hsTnT, and hs CRP , beta- CT x remained independently associated with cardiovascular death/ HF (Q4 versus Q1: adjusted hazard ratio 1.98 [1.34-2.93]) and its components. Beta- CT x correlated weakly with NT -pro BNP ( r=0.17, P<0.001) and left ventricular ejection fraction ( r=-0.05, P=0.008) and did not correlate with hsTnT ( r=0.02, P=0.20), or hs CRP ( r=-0.03, P=0.09). Conclusions Levels of beta- CT x, a biomarker of collagen turnover, were associated with cardiovascular death and HF in patients with non- ST -elevation acute coronary syndrome. This biomarker, which correlated only weakly or not significantly with traditional biomarkers of cardiovascular death and HF , may provide complementary pathobiological insight and risk stratification in these patients.
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http://dx.doi.org/10.1161/JAHA.118.011444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512136PMC
May 2019

exRNA Atlas Analysis Reveals Distinct Extracellular RNA Cargo Types and Their Carriers Present across Human Biofluids.

Cell 2019 04;177(2):463-477.e15

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

To develop a map of cell-cell communication mediated by extracellular RNA (exRNA), the NIH Extracellular RNA Communication Consortium created the exRNA Atlas resource (https://exrna-atlas.org). The Atlas version 4P1 hosts 5,309 exRNA-seq and exRNA qPCR profiles from 19 studies and a suite of analysis and visualization tools. To analyze variation between profiles, we apply computational deconvolution. The analysis leads to a model with six exRNA cargo types (CT1, CT2, CT3A, CT3B, CT3C, CT4), each detectable in multiple biofluids (serum, plasma, CSF, saliva, urine). Five of the cargo types associate with known vesicular and non-vesicular (lipoprotein and ribonucleoprotein) exRNA carriers. To validate utility of this model, we re-analyze an exercise response study by deconvolution to identify physiologically relevant response pathways that were not detected previously. To enable wide application of this model, as part of the exRNA Atlas resource, we provide tools for deconvolution and analysis of user-provided case-control studies.
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http://dx.doi.org/10.1016/j.cell.2019.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616370PMC
April 2019

Small RNA Sequencing across Diverse Biofluids Identifies Optimal Methods for exRNA Isolation.

Cell 2019 04;177(2):446-462.e16

Department of Obstetrics, Gynecology, and Reproductive Sciences and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address:

Poor reproducibility within and across studies arising from lack of knowledge regarding the performance of extracellular RNA (exRNA) isolation methods has hindered progress in the exRNA field. A systematic comparison of 10 exRNA isolation methods across 5 biofluids revealed marked differences in the complexity and reproducibility of the resulting small RNA-seq profiles. The relative efficiency with which each method accessed different exRNA carrier subclasses was determined by estimating the proportions of extracellular vesicle (EV)-, ribonucleoprotein (RNP)-, and high-density lipoprotein (HDL)-specific miRNA signatures in each profile. An interactive web-based application (miRDaR) was developed to help investigators select the optimal exRNA isolation method for their studies. miRDar provides comparative statistics for all expressed miRNAs or a selected subset of miRNAs in the desired biofluid for each exRNA isolation method and returns a ranked list of exRNA isolation methods prioritized by complexity, expression level, and reproducibility. These results will improve reproducibility and stimulate further progress in exRNA biomarker development.
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http://dx.doi.org/10.1016/j.cell.2019.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557167PMC
April 2019

The Extracellular RNA Communication Consortium: Establishing Foundational Knowledge and Technologies for Extracellular RNA Research.

Cell 2019 04;177(2):231-242

Department of Obstetrics, Gynecology, and Reproductive Sciences and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

The Extracellular RNA Communication Consortium (ERCC) was launched to accelerate progress in the new field of extracellular RNA (exRNA) biology and to establish whether exRNAs and their carriers, including extracellular vesicles (EVs), can mediate intercellular communication and be utilized for clinical applications. Phase 1 of the ERCC focused on exRNA/EV biogenesis and function, discovery of exRNA biomarkers, development of exRNA/EV-based therapeutics, and construction of a robust set of reference exRNA profiles for a variety of biofluids. Here, we present progress by ERCC investigators in these areas, and we discuss collaborative projects directed at development of robust methods for EV/exRNA isolation and analysis and tools for sharing and computational analysis of exRNA profiling data.
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http://dx.doi.org/10.1016/j.cell.2019.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601620PMC
April 2019

Circulating MicroRNAs: New Avenues for Heart Failure Classification?

J Am Coll Cardiol 2019 03;73(11):1314-1316

Cardiology Division of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.jacc.2018.10.091DOI Listing
March 2019

Cathelicidin-related antimicrobial peptide protects against myocardial ischemia/reperfusion injury.

BMC Med 2019 02 20;17(1):42. Epub 2019 Feb 20.

Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, 333 Nan Chen Road, Shanghai, 200444, China.

Background: Cathelicidins are a major group of natural antimicrobial peptides which play essential roles in regulating host defense and immunity. In addition to the antimicrobial and immunomodulatory activities, recent studies have reported the involvement of cathelicidins in cardiovascular diseases by regulating inflammatory response and microvascular dysfunction. However, the role of cathelicidins in myocardial apoptosis upon cardiac ischemia/reperfusion (I/R) injury remains largely unknown.

Methods: CRAMP (cathelicidin-related antimicrobial peptide) levels were measured in the heart and serum from I/R mice and in neonatal mouse cardiomyocytes treated with oxygen glucose deprivation/reperfusion (OGDR). Human serum cathelicidin antimicrobial peptide (LL-37) levels were measured in myocardial infarction (MI) patients. The role of CRAMP in myocardial apoptosis upon I/R injury was investigated in mice injected with the CRAMP peptide and in CRAMP knockout (KO) mice, as well as in OGDR-treated cardiomyocytes.

Results: We observed reduced CRAMP level in both heart and serum samples from I/R mice and in OGDR-treated cardiomyocytes, as well as reduced LL-37 level in MI patients. Knockdown of CRAMP enhanced cardiomyocyte apoptosis, and CRAMP KO mice displayed increased infarct size and myocardial apoptosis. In contrast, the CRAMP peptide reduced cardiomyocyte apoptosis and I/R injury. The CRAMP peptide inhibited cardiomyocyte apoptosis by activation of Akt and ERK1/2 and phosphorylation and nuclear export of FoxO3a. c-Jun was identified as a negative regulator of the CRAMP gene. Moreover, lower level of serum LL-37/neutrophil ratio was associated with readmission and/or death in MI patients during 1-year follow-up.

Conclusions: CRAMP protects against cardiomyocyte apoptosis and cardiac I/R injury via activation of Akt and ERK and phosphorylation and nuclear export of FoxO3a. Increasing LL-37 might be a novel therapy for cardiac ischemic injury.
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http://dx.doi.org/10.1186/s12916-019-1268-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381635PMC
February 2019

Bayesian analysis of two methods MALDI-TOF-MS system and culture test in otomycosis infection.

World J Otorhinolaryngol Head Neck Surg 2019 Mar 4;5(1):6-13. Epub 2019 Jan 4.

Central Research Laboratory, Institute of Medical Sciences and Sum Hospital, Siksha 'O' Anusandhan University, Odisha, India.

Objective: Identification of otomycotic fungi using matrix-assisted laser desorption ionization (MALDI) time of flight (TOF) mass spectroscopy (MS) and to quantify pervasive errors with Bayes rule; values of sensitivity and specificity of culture test and MALDI-TOF-MS method are quantified.

Method: Fungi cultured ear discharge samples were identified with culture test and MALDI-TOF-MS system. Minimum inhibitory concentration (MIC) or MEC (minimum effective concentration) for 6 antifungals were determined by antifungal susceptibility testing . With Bayes rule, sensitivity and specificity of both MALDI-TOF MS and culture test methods were computed.

Results: Cultures yielded 42 fungal isolates which were confirmed as species (specified against each species) belonging to 8 genera, 22, sp. 7, 3, 3, mixed sp. 3, sp. 2, sp. 1, and sp.1; and MALDI-TOF-MS system also confirmed those isolates. antifungal susceptibility testing with terms of MIC 50 and MIC 90, isolates fungi were highly susceptible to 6 antifungals; and caspofungin was the most active antifungal. The high value of specificity 84.6%, suggested a limited loss of confidence on the culture test at the absence of an infection, in comparison to MALDI-TOF-MS. Sensitivity of the culture test was 87.5%; this high figure strongly approves the culture test to be the dependable method for the otomycosis diagnosis, when the infection is stable.

Conclusion: Based on sensitivity and specificity together the culture test could be done in face of the gold-standard MALDI-TOF-MS system the estimating both methods.
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http://dx.doi.org/10.1016/j.wjorl.2018.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364575PMC
March 2019

HDAC9 complex inhibition improves smooth muscle-dependent stenotic vascular disease.

JCI Insight 2019 01 24;4(2). Epub 2019 Jan 24.

Cardiovascular Research Center, Cardiology Division, Department of Medicine.

Patients with heterozygous missense mutations in the ACTA2 or MYH11 gene are known to exhibit thoracic aortic aneurysm and a risk of early-onset aortic dissection. However, less common phenotypes involving arterial obstruction are also observed, including coronary and cerebrovascular stenotic disease. Herein we implicate the HDAC9 complex in transcriptional silencing of contractile protein-associated genes, known to undergo downregulation in stenotic lesions. Furthermore, neointimal formation was inhibited in HDAC9- or MALAT1-deficient mice with preservation of contractile protein expression. Pharmacologic targeting of the HDAC9 complex through either MALAT1 antisense oligonucleotides or inhibition of the methyltransferase EZH2 (catalytic mediator recruited by the HDAC9 complex) reduced neointimal formation. In conclusion, we report the implication of the HDAC9 complex in stenotic disease and demonstrate that pharmacologic therapy targeting epigenetic complexes can ameliorate arterial obstruction in an experimental system.
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http://dx.doi.org/10.1172/jci.insight.124706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413784PMC
January 2019