V J Dzau

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

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Publications (532)4100.68 Total impact

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    ABSTRACT: In the past decade, substantial evidence supports the paradigm that stem cells exert their reparative and regenerative effects, in large part, through the release of biologically active molecules acting in a paracrine fashion on resident cells. The data suggest the existence of a tissue microenvironment where stem cell factors influence cell survival, inflammation, angiogenesis, repair, and regeneration in a temporal and spatial manner.
    No preview · Article · Jan 2016 · Circulation Research
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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.
    No preview · Article · Dec 2015
  • 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.
    No preview · Article · Dec 2015
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    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.
    No preview · Article · Nov 2015 · Laboratory Investigation
  • Victor J Dzau

    No preview · Article · Nov 2015 · JAMA The Journal of the American Medical Association
  • 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.
    No preview · Article · Oct 2015 · The Lancet
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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.
    No preview · Article · Oct 2015 · Journal of Biophotonics
  • Victor J Dzau · Kee Chee Soo

    No preview · Article · Sep 2015 · Annals of the Academy of Medicine, Singapore
  • Victor J Dzau · Ralph J Cicerone

    No preview · Article · Jul 2015 · Human gene therapy
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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.
    No preview · Article · Jun 2015 · Journal of the American Society of Hypertension (JASH)
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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.
    No preview · Article · Jun 2015 · Journal of Molecular and Cellular Cardiology
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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.
    No preview · Article · May 2015 · Circulation Research
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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.
    No preview · Article · May 2015 · The Lancet
  • 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.
    No preview · Article · Mar 2015 · Circulation Research
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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.
    No preview · Article · Mar 2015 · Hypertension
  • Victor J Dzau · Harvey V Fineberg

    No preview · Article · Jan 2015 · JAMA The Journal of the American Medical Association
  • T. Unger · U.M. Steckelings · V.J. Dzau
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    ABSTRACT: The Protective Arm of the Renin Angiotensin System: Functional Aspects and Therapeutic Implications is the first comprehensive publication to signal the protective role of a distinct part of the renin-angiotensin system (RAS), providing readers with early insight into a complex system which will become of major medical importance in the near future. Focusing on recent research, The Protective Arm of the Renin Angiotensin System presents a host of new experimental studies on specific components of the RAS, namely angiotensin AT2 receptors (AT2R), the angiotensin (1-7) peptide with its receptor Mas, and the enzyme ACE 2, which exert significant beneficial, health-promoting actions by counterbalancing the well-known harmful arm of the RAS with its classical angiotensin AT1 receptor. This innovative concept of the protective arm of the RAS, examined in this reference, represents an indispensable background and will be a strong support for biomedical students, researchers, cardiologists, surgeons, nephrologists, diabetologists, and endocrinologists, as well as any other physician or researcher concerned with RAS physiology, pathophysiology and clinical implications. Provides a complete understanding of the protective side of the Renin Angiotensin System (RAS) involving angiotensin AT2 receptor, ACE2, and Ang(1-7)/Mas receptor Combines the knowledge of editors who pioneered research on the protective renin angiotensin system including; Dr. Thomas Unger, one of the founders of AT2 receptor research; Dr. Ulrike M. Steckelings, who contributed significantly to first preclinical studies with a novel specific AT2-agonist, and Dr. Robson Santos who pioneered research on angiotensin-(1-7) and its receptor Mas. Shows that the protective RAS axes are able to ameliorate the course of several cardiovascular, renal, metabolic and neurological diseases Provides the basis for the understanding of a novel therapeutic approach to stimulate components of the protective arm of the RAS.
    No preview · Article · Jan 2015
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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.
    No preview · Article · Jan 2015 · Science translational medicine
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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.
    Preview · Article · Oct 2014 · Circulation Research
  • Victor J Dzau · Philip A Pizzo

    No preview · Article · Oct 2014 · JAMA The Journal of the American Medical Association

Publication Stats

41k Citations
4,100.68 Total Impact Points

Institutions

  • 2015
    • Washington DC VA Medical Center
      Washington, Washington, D.C., United States
  • 2014-2015
    • The Washington Institute
      Washington, Washington, D.C., United States
  • 2005-2015
    • Duke University Medical Center
      • • Department of Medicine
      • • Division of Cardiology
      Durham, North Carolina, United States
  • 2004-2015
    • Duke University
      • Department of Medicine
      Durham, North Carolina, United States
    • Technische Universität Dresden
      Dresden, Saxony, Germany
    • University of Glasgow
      • Institute of Cardiovascular and Medical Sciences
      Glasgow, Scotland, United Kingdom
    • Queen's University
      • Department of Physiology
      Kingston, Ontario, Canada
  • 1982-2007
    • Harvard Medical School
      • Department of Medicine
      Boston, MA, United States
  • 1980-2007
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1982-2005
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2001-2002
    • University of Toronto
      • Department of Laboratory Medicine and Pathobiology
      Toronto, Ontario, Canada
  • 1990-1998
    • Stanford University
      • • Division of Cardiovascular Medicine
      • • Falk Cardiovascular Research Center
      Stanford, California, United States
  • 1990-1997
    • Stanford Medicine
      • • Falk Cardiovascular Research Center
      • • Division of Cardiovascular Medicine
      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