Thomas M Vondriska

University of California, Los Angeles, Los Ángeles, California, United States

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Publications (61)401.37 Total impact

  • Emma Monte · Rachel Lopez · Thomas M. Vondriska ·
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    ABSTRACT: The application of proteomics in biology and medicine has reached a moment of truth. The demand of biologists for transformative insights into how cells work, plus the mandate of basic science research to ultimately impact clinical medicine, crystallize as a test on the rigor and reproducibility of any 'omics measurement. Studies like that by Boylston et al. indicate that proteomics can pass that test.
    Journal of Molecular and Cellular Cardiology 11/2015; DOI:10.1016/j.yjmcc.2015.11.022 · 4.66 Impact Factor
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    Thomas M Vondriska ·

    The Journal of Physiology 04/2015; 593(8):1773-1775. DOI:10.1113/JP270143 · 5.04 Impact Factor
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    ABSTRACT: Tightly regulated Ca(2+) homeostasis is a prerequisite for proper cardiac function. To dissect the regulatory network of cardiac Ca(2+) handling, we performed a chemical suppressor screen on zebrafish tremblor embryos, which suffer from Ca(2+) extrusion defects. Efsevin was identified based on its potent activity to restore coordinated contractions in tremblor. We show that efsevin binds to VDAC2, potentiates mitochondrial Ca(2+) uptake and accelerates the transfer of Ca(2+) from intracellular stores into mitochondria. In cardiomyocytes, efsevin restricts the temporal and spatial boundaries of Ca(2+) sparks and thereby inhibits Ca(2+) overload-induced erratic Ca(2+) waves and irregular contractions. We further show that overexpression of VDAC2 recapitulates the suppressive effect of efsevin on tremblor embryos whereas VDAC2 deficiency attenuates efsevin's rescue effect and that VDAC2 functions synergistically with MCU to suppress cardiac fibrillation in tremblor. Together, these findings demonstrate a critical modulatory role for VDAC2-dependent mitochondrial Ca(2+) uptake in the regulation of cardiac rhythmicity.
    eLife Sciences 01/2015; 4(4). DOI:10.7554/eLife.04801 · 9.32 Impact Factor
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    Shuxun Ren · Gang Lu · Asuka Ota · Z Hong Zhou · Thomas M Vondriska · Timothy F Lane · Yibin Wang ·
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    ABSTRACT: We recently reported that the PPM1l gene encodes an endoplasmic reticulum (ER) membrane targeted protein phosphatase (named PP2Ce) with highly specific activity towards Inositol-requiring protein-1 (IRE1) and regulates the functional outcome of ER stress. In the present report, we found that the PP2Ce protein is highly expressed in lactating epithelium of the mammary gland. Loss of PP2Ce in vivo impairs physiological unfolded protein response (UPR) and induces stress kinase activation, resulting in loss of milk production and induction of epithelial apoptosis in the lactating mammary gland. This study provides the first in vivo evidence that PP2Ce is an essential regulator of normal lactation, possibly involving IRE1 signaling and ER stress regulation in mammary epithelium.
    PLoS ONE 11/2014; 9(11):e111606. DOI:10.1371/journal.pone.0111606 · 3.23 Impact Factor
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    ABSTRACT: Endothelial cells contribute to a subset of cardiac fibroblasts by undergoing endothelial-to-mesenchymal transition, but whether cardiac fibroblasts can adopt an endothelial cell fate and directly contribute to neovascularization after cardiac injury is not known. Here, using genetic fate map techniques, we demonstrate that cardiac fibroblasts rapidly adopt an endothelial-cell-like phenotype after acute ischaemic cardiac injury. Fibroblast-derived endothelial cells exhibit anatomical and functional characteristics of native endothelial cells. We show that the transcription factor p53 regulates such a switch in cardiac fibroblast fate. Loss of p53 in cardiac fibroblasts severely decreases the formation of fibroblast-derived endothelial cells, reduces post-infarct vascular density and worsens cardiac function. Conversely, stimulation of the p53 pathway in cardiac fibroblasts augments mesenchymal-to-endothelial transition, enhances vascularity and improves cardiac function. These observations demonstrate that mesenchymal-to-endothelial transition contributes to neovascularization of the injured heart and represents a potential therapeutic target for enhancing cardiac repair.
    Nature 10/2014; 514(7524). DOI:10.1038/nature13839 · 41.46 Impact Factor
  • Elaheh Karbassi · Thomas M. Vondriska ·
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    ABSTRACT: The devastating impact of congenital heart defects has made mechanisms of vertebrate heart and vascular development an active area of study. Because myocyte death is a common feature of acquired cardiovascular diseases and the adult heart does not regenerate, the need exists to understand whether features of the developing heart and vasculature—which are more plastic—can be exploited therapeutically in the disease setting. We know that a core network of transcription factors governs commitment to the cardiovascular lineage, and recent studies using genetic loss-of-function approaches and unbiased genomic studies have revealed the role for various chromatin modulatory events. We reason that chromatin structure itself is a causal feature that influences transcriptome complexity along a developmental continuum, and the purpose of this article is to highlight the areas in which ‘omics technologies have the potential to reveal new principles of phenotypic plasticity in development. We review the major mechanisms of chromatin structural regulation, highlighting what is known about their actions to control cardiovascular differentiation. We discuss emergent mechanisms of regulation that have been identified on the basis of genomic and proteomic studies of cardiac nuclei and identify current challenges to an integrated understanding of chromatin structure and cardiovascular phenotype.This article is protected by copyright. All rights reserved
    Proteomics 10/2014; 14(19). DOI:10.1002/pmic.201400131 · 3.81 Impact Factor
  • Emma Monte · Thomas M Vondriska ·
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    ABSTRACT: Cardiovascular disease is a tremendous burden on human health and results from malfunction of various networks of biological molecules in the context of environmental stress. Despite strong evidence of heritability, many common forms of heart disease (heart failure in particular) have not yielded to genome-wide association studies to identify causative mutations acting via the disruption of individual molecules. Increasing evidence suggests, however, that genetic variation in non-coding regions is strongly linked to disease susceptibility. We hypothesize that epigenomic variation may engender different chromatin environments in the absence of (or in parallel with) changes in protein or mRNA sequence and abundance. In this manner, distinct-genetically encoded-chromatin environments can exhibit distinct responses to environmental stresses that cause heart failure, explaining a significant portion of the altered susceptibility that is observed in human disease. This article is protected by copyright. All rights reserved.
    PROTEOMICS - CLINICAL APPLICATIONS 08/2014; 8(7-8). DOI:10.1002/prca.201400031 · 2.96 Impact Factor
  • Douglas J Chapski · Emma Monte · Thomas M Vondriska ·

    Circulation Research 04/2014; 114(8):1225-7. DOI:10.1161/CIRCRESAHA.114.303785 · 11.02 Impact Factor
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    ABSTRACT: The protein phosphatase 1-like gene (PPM1l) was identified as causal gene for obesity and metabolic abnormalities in mice. However, the underlying mechanisms were unknown. In this report, we find PPM1l encodes an endoplasmic reticulum (ER) membrane targeted protein phosphatase (PP2Ce) and has specific activity to basal and ER stress induced auto-phosphorylation of Inositol-REquiring protein-1 (IRE1). PP2Ce inactivation resulted in elevated IRE1 phosphorylation and higher expression of XBP-1, CHOP, and BiP at basal. However, ER stress stimulated XBP-1 and BiP induction was blunted while CHOP induction was further enhanced in PP2Ce null cells. PP2Ce protein levels are significantly induced during adipogenesis in vitro and are necessary for normal adipocyte maturation. Finally, we provide evidence that common genetic variation of PPM11 gene is significantly associated with human lipid profile. Therefore, PPM1l mediated IRE1 regulation and downstream ER stress signaling is a plausible molecular basis for its role in metabolic regulation and disorder.
    Molecular Metabolism 11/2013; 2(4):405-416. DOI:10.1016/j.molmet.2013.07.005
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    ABSTRACT: Myocyte hypertrophy antecedent to heart failure involves changes in global gene expression, although the preceding mechanisms to coordinate DNA accessibility on a genomic scale are unknown. Chromatin-associated proteins can alter chromatin structure by changing their association with DNA, thereby altering the gene expression profile. Little is known about the global changes in chromatin sub-proteomes that accompany heart failure, and the mechanisms by which these proteins alter chromatin structure. The present study tests the fundamental hypothesis that cardiac growth and plasticity in the setting of disease recapitulates conserved developmental chromatin remodeling events. We used quantitative proteomics to identify chromatin-associated proteins extracted via detergent and to quantify changes in abundance during disease. Our study identified 321 proteins in this sub-proteome, demonstrating it to have modest conservation with that revealed using strong acid. Of these proteins, 176 exhibited altered expression during cardiac hypertrophy and failure; we conducted extensive functional characterization of one of these proteins, Nucleolin. Morpholino-based knockdown of nucleolin abolished protein expression but surprisingly had little impact on gross morphological development. However, zebrafish hearts lacking Nucleolin displayed severe developmental impairment, abnormal chamber patterning and functional deficits, ostensibly due to defects in cardiac looping and myocyte differentiation. The mechanisms underlying these defects involve perturbed BMP4 expression, decreased rRNA transcription and a shift to more heterochromatic chromatin. This study reports the quantitative analysis of a new chromatin sub-proteome in the normal and diseased mouse heart. Validation studies in zebrafish examine the role of Nucleolin to orchestrate genomic reprogramming events shared between development and disease.
    AJP Heart and Circulatory Physiology 09/2013; 305(11). DOI:10.1152/ajpheart.00529.2013 · 3.84 Impact Factor
  • Haodong Chen · Emma Monte · Thomas M Vondriska · Sarah Franklin ·
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    ABSTRACT: Differences in chromatin-associated proteins allow the same genome to participate in multiple cell types and to respond to an array of stimuli in any given cell. To understand the fundamental properties of chromatin and to reveal its cell- and/or stimulus-specific behaviors, quantitative proteomics is an essential technology. This chapter details the methods for fractionation and quantitative mass spectrometric analysis of chromatin from hearts or isolated adult myocytes, detailing some of the considerations for applications to understanding heart disease. The state-of-the-art methodology for data interpretation and integration through bioinformatics is reviewed.
    Methods in molecular biology (Clifton, N.J.) 04/2013; 1005:77-93. DOI:10.1007/978-1-62703-386-2_7 · 1.29 Impact Factor
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    Manuel Rosa-Garrido · Elaheh Karbassi · Emma Monte · Thomas M Vondriska ·
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    ABSTRACT: It has been appreciated for some time that cardiovascular disease involves large-scale transcriptional changes in various cell types. What has become increasingly clear only in the past few years, however, is the role of chromatin remodeling in cardiovascular phenotypes in normal physiology, as well as in development and disease. This review summarizes the state of the chromatin field in terms of distinct mechanisms to regulate chromatin structure in vivo, identifying when these modes of regulation have been demonstrated in cardiovascular tissues. We describe areas in which a better understanding of chromatin structure is leading to new insights into the fundamental biology of cardiovascular disease.
    Circulation Journal 04/2013; 77(6). DOI:10.1253/circj.CJ-13-0176 · 3.94 Impact Factor
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    ABSTRACT: Lacking from the rapidly evolving field of chromatin regulation is a discrete model of chromatin states. We propose that each state in such a model should meet two conditions: a structural component and a quantifiable effect on transcription. The practical benefits to the field of a model with greater than two states (including one with six states, as described herein) would be to improve interpretation of data from disparate organ systems, to reflect temporal and developmental dynamics and to integrate the, at present, conceptually and experimentally disparate analyses of individual genetic loci (in vitro or using single gene approaches) and genome-wide features (including ChlP-seq, chromosomal capture and mRNA expression via microarrays/sequencing).
    FEBS letters 08/2012; 586(20):3548-54. DOI:10.1016/j.febslet.2012.08.018 · 3.17 Impact Factor
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    ABSTRACT: Despite the extensive knowledge of the functional unit of chromatin-the nucleosome-for which structural information exists at the atomic level, little is known about the endogenous structure of eukaryotic genomes. Chromosomal capture techniques and genome-wide chromatin immunoprecipitation and next generation sequencing have provided complementary insight into global features of chromatin structure, but these methods do not directly measure structural features of the genome in situ. This lack of insight is particularly troublesome in terminally differentiated cells which must reorganize their genomes for large scale gene expression changes in the absence of cell division. For example, cardiomyocytes, which are fully committed and reside in interphase, are capable of massive gene expression changes in response to physiological stimuli, but the global changes in chromatin structure that enable such transcriptional changes are unknown. The present study addressed this problem utilizing super-resolution stimulated emission depletion (STED) microscopy to directly measure chromatin features in mammalian cells. We demonstrate that immunolabeling of histone H3 coupled with STED imaging reveals chromatin domains on a scale of 40-70 nm, several folds better than the resolution of conventional confocal microscopy. An analytical workflow is established to detect changes in chromatin structure following acute stimuli and used to investigate rearrangements in cardiomyocyte genomes following agonists that induce cellular hypertrophy. This approach is readily adaptable to investigation of other nuclear features using a similar antibody-based labeling technique and enables direct measurements of chromatin domain changes in response to physiological stimuli.
    Journal of Molecular and Cellular Cardiology 07/2012; 53(4):552-8. DOI:10.1016/j.yjmcc.2012.07.009 · 4.66 Impact Factor
  • Brad Picha · Matthew Thompson · Thomas M Vondriska ·

    Nature 05/2012; 485(7396):41. DOI:10.1038/485041d · 41.46 Impact Factor
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    ABSTRACT: A fundamental question in biology is how genome-wide changes in gene expression are enacted in response to a finite stimulus. Recent studies have mapped changes in nucleosome localization, determined the binding preferences for individual transcription factors, and shown that the genome adopts a nonrandom structure in vivo. What remains unclear is how global changes in the proteins bound to DNA alter chromatin structure and gene expression. We have addressed this question in the mouse heart, a system in which global gene expression and massive phenotypic changes occur without cardiac cell division, making the mechanisms of chromatin remodeling centrally important. To determine factors controlling genomic plasticity, we used mass spectrometry to measure chromatin-associated proteins. We have characterized the abundance of 305 chromatin-associated proteins in normal cells and measured changes in 108 proteins that accompany the progression of heart disease. These studies were conducted on a high mass accuracy instrument and confirmed in multiple biological replicates, facilitating statistical analysis and allowing us to interrogate the data bioinformatically for modules of proteins involved in similar processes. Our studies reveal general principles for global shifts in chromatin accessibility: altered linker to core histone ratio; differing abundance of chromatin structural proteins; and reprogrammed histone post-translational modifications. Using small interfering RNA-mediated loss-of-function in isolated cells, we demonstrate that the non-histone chromatin structural protein HMGB2 (but not HMGB1) suppresses pathologic cell growth in vivo and controls a gene expression program responsible for hypertrophic cell growth. Our findings reveal the basis for alterations in chromatin structure necessary for genome-wide changes in gene expression. These studies have fundamental implications for understanding how global chromatin remodeling occurs with specificity and accuracy, demonstrating that isoform-specific alterations in chromatin structural proteins can impart these features.
    Molecular &amp Cellular Proteomics 01/2012; 11(6):M111.014258. DOI:10.1074/mcp.M111.014258 · 6.56 Impact Factor
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    ABSTRACT: In the nucleus reside the proteomes whose functions are most intimately linked with gene regulation. Adult mammalian cardiomyocyte nuclei are unique due to the high percentage of binucleated cells,(1) the predominantly heterochromatic state of the DNA, and the non-dividing nature of the cardiomyocyte which renders adult nuclei in a permanent state of interphase.(2) Transcriptional regulation during development and disease have been well studied in this organ,(3-5) but what remains relatively unexplored is the role played by the nuclear proteins responsible for DNA packaging and expression, and how these proteins control changes in transcriptional programs that occur during disease.(6) In the developed world, heart disease is the number one cause of mortality for both men and women.(7) Insight on how nuclear proteins cooperate to regulate the progression of this disease is critical for advancing the current treatment options. Mass spectrometry is the ideal tool for addressing these questions as it allows for an unbiased annotation of the nuclear proteome and relative quantification for how the abundance of these proteins changes with disease. While there have been several proteomic studies for mammalian nuclear protein complexes,(8-13) until recently(14) there has been only one study examining the cardiac nuclear proteome, and it considered the entire nucleus, rather than exploring the proteome at the level of nuclear sub compartments.(15) In large part, this shortage of work is due to the difficulty of isolating cardiac nuclei. Cardiac nuclei occur within a rigid and dense actin-myosin apparatus to which they are connected via multiple extensions from the endoplasmic reticulum, to the extent that myocyte contraction alters their overall shape.(16) Additionally, cardiomyocytes are 40% mitochondria by volume(17) which necessitates enrichment of the nucleus apart from the other organelles. Here we describe a protocol for cardiac nuclear enrichment and further fractionation into biologically-relevant compartments. Furthermore, we detail methods for label-free quantitative mass spectrometric dissection of these fractions-techniques amenable to in vivo experimentation in various animal models and organ systems where metabolic labeling is not feasible.
    Journal of Visualized Experiments 01/2012; DOI:10.3791/4294 · 1.33 Impact Factor
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    Sarah Franklin · Thomas M Vondriska ·
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    ABSTRACT: Systems biology, with its associated technologies of proteomics, genomics, and metabolomics, is driving the evolution of our understanding of cardiovascular physiology. Rather than studying individual molecules or even single reactions, a systems approach allows integration of orthogonal data sets from distinct tiers of biological data, including gene, RNA, protein, metabolite, and other component networks. Together these networks give rise to emergent properties of cellular function, and it is their reprogramming that causes disease. We present 5 observations regarding how systems biology is guiding a revisiting of the central dogma: (1) It deemphasizes the unidirectional flow of information from genes to proteins; (2) it reveals the role of modules of molecules as opposed to individual proteins acting in isolation; (3) it enables discovery of novel emergent properties; (4) it demonstrates the importance of networks in biology; and (5) it adds new dimensionality to the study of biological systems.
    Circulation Cardiovascular Genetics 10/2011; 4(5):576. DOI:10.1161/CIRCGENETICS.110.957795 · 4.60 Impact Factor
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    ABSTRACT: As host to the genome, the nucleus plays a critical role as modulator of cellular phenotype. To understand the totality of proteins that regulate this organelle, we used proteomics to characterize the components of the cardiac nucleus. Following purification, cardiac nuclei were fractionated into biologically relevant fractions including acid-soluble proteins, chromatin-bound molecules and nucleoplasmic proteins. These distinct subproteomes were characterized by liquid chromatography-tandem MS. We report a cardiac nuclear proteome of 1048 proteins--only 146 of which are shared between the distinct subcompartments of this organelle. Analysis of genomic loci encoding these molecules gives insights into local hotspots for nuclear protein regulation. High mass accuracy and complementary analytical techniques allowed the discrimination of distinct protein isoforms, including 54 total histone variants, 17 of which were distinguished by unique peptide sequences and four of which have never been detected at the protein level. These studies are the first unbiased analysis of cardiac nuclear subcompartments and provide a foundation for exploration of this organelle's proteomes during disease.
    Molecular &amp Cellular Proteomics 01/2011; 10(1):M110.000703. DOI:10.1074/mcp.M110.000703 · 6.56 Impact Factor

Publication Stats

2k Citations
401.37 Total Impact Points


  • 2003-2015
    • University of California, Los Angeles
      • • Department of Anesthesiology
      • • Department of Physiology
      • • Department of Medicine
      • • Division of Cardiology
      Los Ángeles, California, United States
  • 2008
    • UCLA Cardiovascular Research Laboratory
      Los Angeles, California, United States
  • 2004
    • CSU Mentor
      Long Beach, California, United States
  • 2001-2002
    • University of Louisville
      • • Department of Medicine
      • • Department of Physiology and Biophysics
      Louisville, Kentucky, United States