V J Dzau

Washington DC VA Medical Center, Washington, Washington, D.C., United States

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Publications (509)3916.6 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Nuclear hormone receptor liver X receptor-alpha (LXRα) has a vital role in cholesterol homeostasis and is reported to have a role in adipose function and obesity although this is controversial. Conversely, mesenchymal stem cells (MSCs) are suggested to be a major source of adipocyte generation. Accordingly, we examined the role of LXRα in adipogenesis of MSCs. Adult murine MSCs (mMSCs) were isolated from wild-type (WT) and LXR-null mice. Using WT mMSCs, we further generated cell lines stably overexpressing GFP-LXRα (mMSC/LXRα/GFP) or GFP alone (mMSC/GFP) by retroviral infection. Confluent mMSCs were differentiated into adipocytes by the established protocol. Compared with MSCs isolated from WT mice, MSCs from LXR-null mice showed significantly increased adipogenesis, as determined by lipid droplet accumulation and adipogenesis-related gene expression. Moreover, mMSCs stably overexpressing GFP-LXRα (mMSC/LXRα/GFP) exhibited significantly decreased adipogenesis compared with mMSCs overexpressing GFP alone (mMSC/GFP). Since Wnt/beta-catenin signaling is reported to inhibit adipogenesis, we further examined it. The LXR-null group showed significantly decreased Wnt expression accompanied by a decrease of cellular beta-catenin (vs WT). The mMSC/LXRα/GFP group exhibited significantly increased Wnt expression accompanied by an increase of cellular beta-catenin (vs mMSC/GFP). These data demonstrate that LXRα has an inhibitory effect on adipogenic differentiation in mMSCs with Wnt/beta-catenin signaling. These results provide important insights into the pathophysiology of obesity and obesity-related consequences such as metabolic syndrome and may identify potential therapeutic targets.
    Laboratory Investigation 11/2015; DOI:10.1038/labinvest.2015.141 · 3.68 Impact Factor
  • Victor J Dzau ·
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    ABSTRACT: National science and medical academies across the world serve a range of roles and functions. In particular, the benefits of an independent academy tasked with the provision of formal advice are compelling. For nearly half a century, the Institute of Medicine (IOM) has served the USA and the world by providing independent, authoritative advice on issues related to health and medicine. Its influence reaches deep into the health and policy worlds. This paper provides insight into the principles, processes, and governance that confer unique credibility to IOM advice. The IOM can serve as a useful model for other academies to consider for strengthening their work or when other countries contemplate the creation of a new academy.
    The Lancet 10/2015; DOI:10.1016/S0140-6736(15)00468-7 · 45.22 Impact Factor
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    ABSTRACT: High-resolution tracking of stem cells remains a challenging task. An ultra-bright contrast agent with extended intracellular retention is suitable for in vivo high-resolution tracking of stem cells following the implantation. Here, a plasmonic-active nanoplatform was developed for tracking mesenchymal stromal cells (MSCs) in mice. The nanoplatform consisted of TAT peptide-functionalized gold nanostars (TAT-GNS) that emit ultra-bright two-photon photoluminescence capable of tracking MSCs under high-resolution optical imaging. In vitro experiment showed TAT-GNS-labeled MSCs retained a similar differentiability to that of non-labeled MSCs controls. Due to their star shape, TAT-GNS exhibited greater intracellular retention than that of commercial Q-Tracker. In vivo imaging of TAT-GNS-labeled MSCs five days following intra-arterial injections in mice kidneys showed possible MSCs implantation in juxta-glomerular (JG) regions, but non-specifically in glomeruli and afferent arterioles as well. With future design to optimize GNS labeling specificity and clearance, plasmonic-active nanoplatforms may be a useful intracellular tracking tool for stem cell research.
    Journal of Biophotonics 10/2015; DOI:10.1002/jbio.201500173 · 4.45 Impact Factor
  • Victor J Dzau · Ralph J Cicerone ·

    Human gene therapy 07/2015; 26(7):411-2. DOI:10.1089/hum.2015.29004.vjd · 3.76 Impact Factor
  • Kenichi Matsushita · Yaojiong Wu · Richard E. Pratt · Victor J. Dzau ·
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    ABSTRACT: Recent evidence indicates that the vasculature contains mesenchymal stem cells (MSCs). We hypothesized that angiotensin II (Ang II) type 2 receptors (AT2Rs) play a role in the osteogenesis of MSCs and may have a role in vascular calcification. Human MSCs were differentiated into osteoblasts. Expression of AT2R was significantly increased during osteogenesis, whereas the expression of Ang II type 1 receptors was not significantly changed. Incubation with the AT2R blocker PD123319 with or without Ang II significantly inhibited calcium deposition, whereas type 1 receptor blocker valsartan had no significant effect. PD123319 inhibited extracellular signal-regulated kinase (ERK) phosphorylation in the osteogenic process, whereas valsartan had no effect. Furthermore, PD123319 combined with Ang II also inhibited acute ERK phosphorylation in MSCs induced by insulin. In conclusion, AT2R is upregulated during osteogenesis. Blockade of AT2R inhibits osteogenesis and ERK phosphorylation of human MSCs. These results provide a novel insight into the pathophysiology of calcific vascular disease. Copyright © 2015 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.
    Journal of the American Society of Hypertension (JASH) 06/2015; 9(7). DOI:10.1016/j.jash.2015.06.006 · 2.61 Impact Factor
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    ABSTRACT: Wnt signaling has recently emerged as an important regulator of cardiac progenitor cell proliferation and differentiation, but the exact mechanisms by which Wnt signaling modulates these effects are not known. Understanding these mechanisms is essential for advancing our knowledge of cardiac progenitor cell biology and applying this knowledge to enhance cardiac therapy. Here, we explored the effects of Sfrp2, a canonical Wnt inhibitor, in adult cardiac progenitor cell (CPC) differentiation and investigated the molecular mechanisms involved. Our data show that Sfrp2 treatment can promote differentiation of CPCs after ischemia-reperfusion injury. Treatment of CPCs with Sfrp2 inhibited CPC proliferation and primed them for cardiac differentiation. Sfrp2 binding to Wnt6 and inhibition of Wnt6 canonical pathway was essential for the inhibition of CPC proliferation. This inhibition of Wnt6 canonical signaling by Sfrp2 was important for activation of the non-canonical Wnt/Planar Cell Polarity (PCP) pathway through JNK, which in turn induced expression of cardiac transcription factors and CPC differentiation. Taken together, these results demonstrate a novel role of Sfrp2 and Wnt6 in regulating the dynamic process of CPC proliferation and differentiation, as well as providing new insights into the mechanisms of Wnt signaling in cardiac differentiation. Copyright © 2015. Published by Elsevier Ltd.
    Journal of Molecular and Cellular Cardiology 06/2015; 85. DOI:10.1016/j.yjmcc.2015.06.003 · 4.66 Impact Factor
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    ABSTRACT: The human heart has a limited capacity to regenerate lost or damaged cardiomyocytes after cardiac insult. Instead, myocardial injury is characterized by extensive cardiac remodeling by fibroblasts, resulting in the eventual deterioration of cardiac structure and function. Cardiac function would be improved if these fibroblasts could be converted into cardiomyocytes. MicroRNAs (miRNAs), small noncoding RNAs that promote mRNA degradation and inhibit mRNA translation, have been shown to be important in cardiac development. Using this information, various researchers have used miRNAs to promote the formation of cardiomyocytes through several approaches. Several miRNAs acting in combination promote the direct conversion of cardiac fibroblasts into cardiomyocytes. Moreover, several miRNAs have been identified that aid the formation of inducible pluripotent stem cells and miRNAs also induce these cells to adopt a cardiac fate. MiRNAs have also been implicated in resident cardiac progenitor cell differentiation. In this review, we discuss the current literature as it pertains to these processes, as well as discussing the therapeutic implications of these findings. © 2015 American Heart Association, Inc.
    Circulation Research 05/2015; 116(10):1700-1711. DOI:10.1161/CIRCRESAHA.116.304377 · 11.02 Impact Factor
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    ABSTRACT: Personalised medicine has generated global policy interest in the past few years. In 2012, the European Union established the European Alliance for Personalised Medicine with the aim to accelerate the development, delivery, and uptake of personalised health care, broadly defined. In the same year, the UK's Medical Research Council and National Institute for Health Research funded the National Phenome Centre to deliver broad access to a world-class capability in metabolic phenotyping for biomarker discovery and validation, improved patient stratification, and early identification of drug efficacy and safety.
    The Lancet 05/2015; DOI:10.1016/S0140-6736(15)60722-X · 45.22 Impact Factor
  • Conrad P Hodgkinson · Victor J Dzau ·
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    ABSTRACT: The capacity of the adult mammalian heart to repair itself after injury is limited. In contrast, lower vertebrates such as Zebrafish can completely regenerate the organ after damage. A recent article from Aguirre et al1 in Cell Stem Cell shows that this difference is because of a microRNA program that is active in Zebrafish but silent in mammals. Crucially, reactivation of this dormant microRNA program in the murine heart induces regeneration of the myocardium.
    Circulation Research 03/2015; 116(7):1109-1111. DOI:10.1161/CIRCRESAHA.115.305852 · 11.02 Impact Factor
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    ABSTRACT: Despite the importance of juxtaglomerular cell recruitment in the pathophysiology of cardiovascular diseases, the mechanisms that underlie renin production under conditions of chronic stimulation remain elusive. We have previously shown that CD44+ mesenchymal-like cells (CD44+ cells) exist in the adult kidney. Under chronic sodium deprivation, these cells are recruited to the juxtaglomerular area and differentiate to new renin-expressing cells. Given the proximity of macula densa to the juxtaglomerular area and the importance of macula densa released prostanoids in renin synthesis and release, we hypothesized that chronic sodium deprivation induces macula densa release of prostanoids, stimulating renal CD44+ cell activation and differentiation. CD44+ cells were isolated from adult kidneys and cocultured with the macula densa cell line, MMDD1, in normal or low-sodium medium. Low sodium stimulated prostaglandin E2 production by MMDD1 and induced migration of CD44+ cells. These effects were inhibited by addition of a cyclooxygenase 2 inhibitor (NS398) or an E-prostanoid receptor 4 antagonist (AH23848) to MMDD1 or CD44+ cells, respectively. Addition of prostaglandin E2 to CD44+ cells increased cell migration and induced renin expression. In vivo activation of renal CD44+ cells during juxtaglomerular recruitment was attenuated in wild-type mice subjected to salt restriction in the presence of cyclooxygenase 2 inhibitor rofecoxib. Similar results were observed in E-prostanoid receptor 4 knockout mice subjected to salt restriction. These results show that the prostaglandin E2/E-prostanoid receptor 4 pathway plays a key role in the activation of renal CD44+ mesenchymal stromal cell-like cells during conditions of juxtaglomerular recruitment; highlighting the importance of this pathway as a key regulatory mechanism of juxtaglomerular recruitment. © 2015 American Heart Association, Inc.
    Hypertension 03/2015; 65(5). DOI:10.1161/HYPERTENSIONAHA.114.04611 · 6.48 Impact Factor
  • Victor J Dzau · Harvey V Fineberg ·

    JAMA The Journal of the American Medical Association 01/2015; 313(2):143-4. DOI:10.1001/jama.2014.17660 · 35.29 Impact Factor
  • Victor J. Dzau · William F. ElLaissi · Krishna Udayakumar ·
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    ABSTRACT: To continue meeting their missions, academic health centers must make bold transformative changes. They must extensively reform their systems for care delivery and financing, improve the productivity of research, and reduce the cost of medical education. And they must foster innovation that yields "disruptive" technologies and approaches that can reduce costs and/or increase revenues.
  • Thomas Unger · Ulrike M. Steckelings · Victor J. Dzau ·
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    ABSTRACT: Since its discovery, 25 years ago, the angiotensin AT2 receptor (AT2R) has puzzled the scientific community because of its distinct -localization, regulation, signaling pathways, and biological effects separating it clearly from the classical features of the renin-angiotensin system (RAS) mediated by the angiotensin AT1 receptor. Intensive research over the years has revealed major characteristics of the AT2R as a modulatory player involved in antiproliferation, anti-inflammation, natriuresis, neuroregeneration, and apoptosis, that is, -biological programs that can counterbalance pathological processes and enable recovery from disease. The AT2R has thus mutated from an "-enigmatic" receptor to a significant member of the "protective arm" of the RAS. The recent development of novel, small molecule- and peptide-derived AT2R agonists offers a therapeutic potential in humans with a variety of clinical indications.
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    ABSTRACT: Around the world, innovative genomic-medicine programs capitalize on singular capabilities arising from local health care systems, cultural or political milieus, and unusual selected risk alleles or disease burdens. Such individual efforts might benefit from the sharing of approaches and lessons learned in other locales. The U.S. National Human Genome Research Institute and the National Academy of Medicine recently brought together 25 of these groups to compare projects, to examine the current state of implementation and desired near-term capabilities, and to identify opportunities for collaboration that promote the responsible practice of genomic medicine. Efforts to coalesce these groups around concrete but compelling signature projects should accelerate the responsible implementation of genomic medicine in efforts to improve clinical care worldwide.
    Science translational medicine 01/2015; 7(290):290ps13-290ps13. · 15.84 Impact Factor
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    ABSTRACT: Rationale: A major goal for the treatment of heart tissue damaged by cardiac injury is to develop strategies for restoring healthy heart muscle through the regeneration and repair of damaged myocardium. We recently demonstrated that administration of a specific combination of microRNAs (miR combo) into the infarcted myocardium leads to direct in vivo reprogramming of noncardiac myocytes to cardiac myocytes. However, the biological and functional consequences of such reprogramming are not yet known. Objective: The aim of this study was to determine whether noncardiac myocytes directly reprogrammed using miRNAs in vivo develop into mature functional cardiac myocytes in situ, and whether reprogramming leads to improvement of cardiac function. Methods and results: We subjected fibroblast-specific protein 1-Cre mice/tandem dimer Tomato (tdTomato) mice to cardiac injury by permanent ligation of the left anterior descending coronary artery and injected lentiviruses encoding miR combo or a control nontargeting miRNA. miR combo significantly increased the number of reprogramming events in vivo. Five to 6 weeks after injury, morphological and physiological properties of tdTomato(-) and tdTomato(+) cardiac myocyte-like cells were analyzed ex vivo. tdTomato(+) cells expressed cardiac myocyte markers, sarcomeric organization, excitation-contraction coupling, and action potentials characteristic of mature ventricular cardiac myocytes (tdTomato(-) cells). Reprogramming was associated with improvement of cardiac function, as analyzed by serial echocardiography. There was a time delayed and progressive improvement in fractional shortening and other measures of ventricular function, indicating that miR combo promotes functional recovery of damaged myocardium. Conclusions: The findings from this study further validate the potential use of miRNA-mediated reprogramming as a therapeutic approach to promote cardiac regeneration after myocardial injury.
    Circulation Research 10/2014; 116(3). DOI:10.1161/CIRCRESAHA.116.304510 · 11.02 Impact Factor
  • Victor J Dzau · Philip A Pizzo ·

    JAMA The Journal of the American Medical Association 10/2014; 312(15):1507-1508. DOI:10.1001/jama.2014.12986 · 35.29 Impact Factor
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    ABSTRACT: Rationale: Cardiac progenitor cells (CPCs) are thought to differentiate into the major cell types of the heart: cardiomyocytes, smooth muscle cells, and endothelial cells. We have recently identified ABI family, member 3 (NESH) binding protein (Abi3bp) as a protein important for mesenchymal stem cell biology. Because CPCs share several characteristics with mesenchymal stem cells, we hypothesized that Abi3bp would similarly affect CPC differentiation and proliferation. Objective: To determine whether Abi3bp regulates CPC proliferation and differentiation. Methods and results: In vivo, genetic ablation of the Abi3bp gene inhibited CPC differentiation, whereas CPC number and proliferative capacity were increased. This correlated with adverse recovery after myocardial infarction. In vitro, CPCs, either isolated from Abi3bp knockout mice or expressing an Abi3bp shRNA construct, displayed a higher proliferative capacity and, under differentiating conditions, reduced expression of both early and late cardiomyocyte markers. Abi3bp controlled CPC differentiation via integrin-β1, protein kinase C-ζ, and v-akt murine thymoma viral oncogene homolog. Conclusions: We have identified Abi3bp as a protein important for CPC differentiation and proliferation.
    Circulation Research 10/2014; 115(12). DOI:10.1161/CIRCRESAHA.115.304216 · 11.02 Impact Factor
  • Tilanthi Jayawardena · Maria Mirotsou · Victor J Dzau ·
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    ABSTRACT: The therapeutic administration of microRNAs represents an innovative reprogramming strategy with which to advance cardiac regeneration and personalized medicine. Recently, a distinct set of microRNAs was found capable of converting murine fibroblasts to cardiomyocyte-like cells in vitro. Further treatment with JAK inhibitor I significantly enhanced the efficiency of the microRNA-mediated reprogramming (Jayawardena et al., Circ Res 110(11):1465-1473, 2012). This novel technique serves as an initial tool for switching the cell fate of cardiac fibroblasts toward the cardiomyocyte lineage using microRNAs. As the budding field of reprogramming biology develops, we hope that a thorough examination of the chemical, physical, and temporal parameters determining reprogramming efficiency and maturation will enable a better understanding of the mechanisms governing cardiac cell fate and provide new approaches for drug discovery and therapy for cardiovascular diseases.
    Methods in molecular biology (Clifton, N.J.) 04/2014; 1150:263-72. DOI:10.1007/978-1-4939-0512-6_18 · 1.29 Impact Factor
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    ABSTRACT: Despite advances in the treatment of acute tissue ischemia significant challenges remain in effective cytoprotection from ischemic cell death. It has been documented that injected stem cells, such as mesenchymal stem cells (MSCs), can confer protection to ischemic tissue through the release of paracrine factors. The study of these factors is essential for understanding tissue repair and the development of new therapeutic approaches for regenerative medicine. We have recently shown that a novel factor secreted by MSCs, which we called HASF (Hypoxia and Akt induced Stem cell Factor), promotes cardiomyocyte proliferation. In this study we show that HASF has a cytoprotective effect on ischemia induced cardiomyocyte death. We assessed whether HASF could potentially be used as a therapeutic agent to prevent the damage associated with myocardial infarction. In vitro treatment of cardiomyocytes with HASF protein resulted in decreased apoptosis; TUNEL positive nuclei were fewer in number, and caspase activation and mitochondrial pore opening were inhibited. Purified HASF protein was injected into the heart immediately following myocardial infarction. Heart function was found to be comparable to sham operated animals one month following injury and fibrosis was significantly reduced. In vivo and in vitro HASF activated protein kinase C ε (PKCε). Inhibition of PKCε blocked the HASF effect on apoptosis. Furthermore, the beneficial effects of HASF were lost in mice lacking PKCε. Collectively these results identify HASF as a protein of significant therapeutic potential, acting in part through PKCε.
    Journal of Molecular and Cellular Cardiology 11/2013; 66. DOI:10.1016/j.yjmcc.2013.11.010 · 4.66 Impact Factor
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    ABSTRACT: With a changing health care landscape and a growing gap between the excess costs of fulfilling academic health centers' missions and the available funding, the integrity of those missions is in jeopardy. Profound changes are needed in AHCs' organization and operations. Academic health centers (AHCs) have long led the advancement of science and medicine by pursuing missions of clinical care, research, and education. AHCs have been places where important fundamental and translational research is performed and medical innovations are created and tested. Given the dramatic changes ahead in health care and deteriorating research funding, can this record of achievement continue, or do AHCs in the United States face a growing risk of extinction?(1) Despite their substantial societal value, these centers have an uncertain future. The health care landscape is changing rapidly owing to the Affordable Care Act, state budget deficits, and ...
    New England Journal of Medicine 09/2013; 369(11):991-3. DOI:10.1056/NEJMp1302374 · 55.87 Impact Factor

Publication Stats

38k Citations
3,916.60 Total Impact Points


  • 2015
    • Washington DC VA Medical Center
      Washington, Washington, D.C., United States
  • 2014
    • The Washington Institute
      Washington, Washington, D.C., United States
  • 2005-2013
    • Duke University
      • Department of Medicine
      Durham, North Carolina, United States
    • Duke University Medical Center
      • • Department of Medicine
      • • Division of Cardiology
      Durham, North Carolina, United States
  • 2003-2007
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1982-2007
    • Harvard Medical School
      • Department of Medicine
      Boston, MA, United States
  • 1982-2005
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2004
    • Queen's University
      • Department of Physiology
      Kingston, Ontario, Canada
    • University of California, San Francisco
      • Division of Adult Cardiothoracic Surgery
      San Francisco, CA, United States
    • University of Glasgow
      • Institute of Cardiovascular and Medical Sciences
      Glasgow, Scotland, United Kingdom
  • 2001
    • University of Toronto
      • Department of Laboratory Medicine and Pathobiology
      Toronto, Ontario, Canada
  • 1999
    • Justus-Liebig-Universität Gießen
      Gieben, Hesse, Germany
  • 1990-1997
    • Stanford Medicine
      • • Falk Cardiovascular Research Center
      • • Division of Cardiovascular Medicine
      Stanford, California, United States
    • Stanford University
      • • Division of Cardiovascular Medicine
      • • Falk Cardiovascular Research Center
      Stanford, California, United States
  • 1996
    • Osaka University
      Suika, Ōsaka, Japan
  • 1980-1996
    • Massachusetts General Hospital
      • • Cardiovascular Research Center
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 1995
    • Case Western Reserve University
      Cleveland, Ohio, United States
  • 1993
    • Osaka City University
      • Graduate School of Medicine
      Ōsaka, Ōsaka, Japan
  • 1992
    • University of Florida
      Gainesville, Florida, United States
  • 1991
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
    • Universität Heidelberg
      • Department of Clinical Pharmacology
      Heidelburg, Baden-Württemberg, Germany
  • 1989
    • National Institute for Biological Standards and Control
      Potters Bar, England, United Kingdom
  • 1987-1989
    • University of Massachusetts Boston
      Boston, Massachusetts, United States