Bruce M McManus

Centre of Excellence for the Prevention of Organ Failure (PROOF), Vancouver, British Columbia, Canada

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Publications (322)1455.91 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Cardiac fibrosis is observed across diverse etiologies of heart failure. Granzyme B (GzmB) is a serine protease involved in cell-mediated cytotoxicity in conjunction with the pore-forming protein, perforin. Recent evidence suggests that GzmB also contributes to matrix remodeling and fibrosis through an extracellular, perforin-independent process. However, the role of GzmB in the onset and progression of cardiac fibrosis remains elusive. The present study investigated the role of GzmB in the pathogenesis of cardiac fibrosis. GzmB was elevated in fibrotic human hearts and in angiotensin II-induced murine cardiac fibrosis. Genetic deficiency of GzmB reduced angiotensin II-induced cardiac hypertrophy and fibrosis, independently of perforin. GzmB deficiency also reduced microhemorrhage, inflammation, and fibroblast accumulation in vivo. In vitro, GzmB cleaved the endothelial junction protein, VE-cadherin, resulting in the disruption of endothelial barrier function. Together, these results suggest a perforin-independent, extracellular role for GzmB in the pathogenesis of cardiac fibrosis.
    American Journal Of Pathology 11/2015; DOI:10.1016/j.ajpath.2015.09.010 · 4.59 Impact Factor

  • PLoS ONE 10/2015; 10(10):e0140022. DOI:10.1371/journal.pone.0140022 · 3.23 Impact Factor
  • S. Chatur · B. Wong · J. Carthy · B.M. McManus ·

    The Canadian journal of cardiology 10/2015; 31(10):S201. DOI:10.1016/j.cjca.2015.07.424 · 3.94 Impact Factor
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    ABSTRACT: Objective Versican is a versatile and highly interactive chondroitin sulfate proteoglycan that is found in the extracellular matrix (ECM) of many tissues and is a major component of developing and developed lesions in atherosclerotic vascular disease. In this paper, we present data to indicate that versican may have important intracellular functions in addition to its better known roles in the ECM. Methods and Results Rat aortic smooth muscle cells were fixed and immunostained for versican and images of fluorescently labeled cells were obtained by confocal microscopy. Intracellular versican was detected in the nucleus and cytosol of vascular smooth muscle cells. The use of a synthetic neutralizing peptide eliminated versican immunostaining, demonstrating the specificity of the antibody used in this study. Western blot of pure nuclear extracts confirmed the presence of versican in the nucleus, and multi-fluorescent immunostaining showed strong colocalization of versican and nucleolin, suggesting a nucleolar localization of versican in non-dividing cells. In dividing valve interstitial cells, a strong signal for versican was observed in and around the condensed chromosomes during the various stages of mitosis. Multi-fluorescent immunostaining for versican and tubulin revealed versican aggregated at opposing poles of the mitotic spindle during metaphase. Knockdown of versican expression using siRNA disrupted the organization of the mitotic spindle and led to the formation of multipolar spindles during metaphase. Conclusions Collectively, these data suggest an intracellular function for versican in vascular cells where it appears to play a role in mitotic spindle organization during cell division. These observations open a new avenue for studies of versican, suggesting even more diverse roles in vascular health and disease.
    Cardiovascular Pathology 07/2015; DOI:10.1016/j.carpath.2015.07.010 · 2.00 Impact Factor
  • Don D Sin · Zsuzsanna Hollander · Mari L DeMarco · Bruce M McManus · Raymond T Ng ·
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is one of the major causes of morbidity and mortality in the world. Regrettably, there are no biomarkers to objectively diagnose COPD exacerbations, which are the major drivers of hospitalization and deaths from COPD. Moreover, there are no biomarkers to guide therapeutic choices or to risk-stratify patients for imminent exacerbations and no objective biomarkers of disease activity or disease progression. While there has been a tremendous investment in COPD biomarker discovery over the past two decades, clinical translation and implementation has not matched these efforts. In this article, we outline the challenges of biomarker development in COPD and provide an overview of a developmental pipeline that may be able to surmount these challenges and bring novel biomarker solutions to accelerate therapeutic discoveries and to improve the care and outcomes of the millions of individuals worldwide with COPD.
    American Journal of Respiratory and Critical Care Medicine 07/2015; DOI:10.1164/rccm.201505-0871PP · 13.00 Impact Factor
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    ABSTRACT: Background Versican, a chondroitin sulphate proteoglycan, is one of the key components of the provisional extracellular matrix expressed after injury. The current study evaluated the hypothesis that a versican-rich matrix alters the phenotype of cultured fibroblasts. Methods and Results The full-length cDNA for the V1 isoform of human versican was cloned and the recombinant proteoglycan was expressed in murine fibroblasts. Versican expression induced a marked change in fibroblast phenotype. Functionally, the versican-expressing fibroblasts proliferated faster and displayed enhanced cell adhesion, but migrated slower than control cells. These changes in cell function were associated with greater N-cadherin and integrin β1 expression, along with increased FAK phosphorylation. The versican-expressing fibroblasts also displayed expression of smooth muscle α-actin, a marker of myofibroblast differentiation. Consistent with this observation, the versican fibroblasts displayed increased synthetic activity, as measured by collagen III mRNA expression, as well as a greater capacity to contract a collagen lattice. These changes appear to be mediated, at least in part, by an increase in active TGF-β signaling in the versican expressing fibroblasts, and this was measured by phosphorylation and nuclear accumulation of SMAD2. Conclusions Collectively, these data indicate versican expression induces a myofibroblast-like phenotype in cultured fibroblasts.
    PLoS ONE 07/2015; 10(7). DOI:10.1371/journal.pone.0133056 · 3.23 Impact Factor
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    Anna Meredith · Seti Boroomand · Jon Carthy · Zongshu Luo · Bruce McManus ·
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    ABSTRACT: Epidemiological and interventional studies have suggested a protective role for vitamin D in cardiovascular disease, and basic research has implicated vitamin D as a potential inhibitor of fibrosis in a number of organ systems; yet little is known regarding direct effects of vitamin D on human cardiac cells. Given the critical role of fibrotic responses in end stage cardiac disease, we examined the effect of active vitamin D treatment on fibrotic responses in primary human adult ventricular cardiac fibroblasts (HCF-av), and investigated the relationship between circulating vitamin D (25(OH)D3) and cardiac fibrosis in human myocardial samples. Interstitial cardiac fibrosis in end stage HF was evaluated by image analysis of picrosirius red stained myocardial sections. Serum 25(OH)D3 levels were assayed using mass spectrometry. Commercially available HCF-av were treated with transforming growth factor (TGF)β1 to induce activation, in the presence or absence of active vitamin D (1,25(OH)2D3). Functional responses of fibroblasts were analyzed by in vitro collagen gel contraction assay. 1,25(OH)2D3 treatment significantly inhibited TGFβ1-mediated cell contraction, and confocal imaging demonstrated reduced stress fiber formation in the presence of 1,25(OH)2D3. Treatment with 1,25(OH)2D3 reduced alpha-smooth muscle actin expression to control levels and inhibited SMAD2 phosphorylation. Our results demonstrate that active vitamin D can prevent TGFβ1-mediated biochemical and functional pro-fibrotic changes in human primary cardiac fibroblasts. An inverse relationship between vitamin D status and cardiac fibrosis in end stage heart failure was observed. Collectively, our data support an inhibitory role for vitamin D in cardiac fibrosis.
    PLoS ONE 06/2015; 10(6):e0128655. DOI:10.1371/journal.pone.0128655 · 3.23 Impact Factor
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    ABSTRACT: Up-to-date estimates of burden of diseases are required for evidence-based policy making. The objectives of this study were to determine the excess costs of chronic obstructive pulmonary disease (COPD) and its trend from 2001 to 2010 in British Columbia, Canada. We used British Columbia's administrative health data to construct a cohort of patients with COPD and a matched comparison cohort of non-COPD subjects. We followed each individual from the time of first COPD-related health care event (or equivalent time for the comparison cohort). Direct medical costs (in 2010 Canadian dollars [$]) were calculated based on billing records pertaining to hospital admissions, outpatient services use, medication dispensations, and community care services. We determined the excess medical costs of COPD by calculating the difference in overall medical costs between the COPD and the comparison cohort. 153,570 and 246,801 individuals constituted the COPD and comparison cohorts, respectively (for both cohorts: mean age at entry 66.9, 47.2% female). The excess costs of COPD during the study period were $5,452 per patient-year. Inpatient, outpatient, medication, and community care costs were responsible for 57%, 16%, 22%, and 5% of the excess costs, respectively. Excess costs increased by $296/person-year (P<0.01), with hospital costs demonstrating the largest increase over time ($258/person-year, P<0.01). The direct economic burden of COPD is high and has increased significantly between 2001 and 2010 over and above the increase in the health care costs of the general population. Further investigation is required to elucidate the underlying reasons for the temporal increase in COPD direct costs.
    Chest 06/2015; 148(3). DOI:10.1378/chest.15-0721 · 7.48 Impact Factor
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    ABSTRACT: ABSTRACT Viruses such as coxsackievirus B3 (CVB3) are entirely host cell-dependent parasites. Indeed, they must cleverly exploit various compartments of host cells to complete their life cycle, and consequently launch disease. Evolution has equipped this pico-rna-virus, CVB3, to use different strategies, including CVB3-induced direct damage to host cells followed by a host inflammatory response to CVB3 infection, and cell death to super-additively promote target organ tissue injury, and dysfunction. In this update, the patho-stratagems of CVB3 are explored from molecular, and systems-level approaches. In summarizing recent developments in this field, we focus particularly on mechanisms by which CVB3 can harness different host cell processes including kinases, host cell-killing and cell-eating machineries, matrix metalloproteinases and miRNAs to promote disease.
    Future Microbiology 04/2015; 10(4):629-53. DOI:10.2217/fmb.15.5 · 4.28 Impact Factor
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    ABSTRACT: AimsAnderson–Fabry disease (AFD) is an important X-linked metabolic disease resulting in progressive end-organ involvement, with cardiac disease being the dominant determinant of survival in a gender-dependent manner. Recent epidemiological screening for AFD suggests the prevalence is much higher than previously recognized, with estimates of 1:3000. Our aim was to discover novel plasma biomarker signatures in adult patients with AFD.Methods and resultsWe used an unbiased proteomic screening approach to discover novel plasma biomarker signatures. In the discovery cohort of 46 subjects, 14 healthy controls and 32 patients with AFD, we used a mass spectrometry iTRAQ proteomic approach followed by multiple reaction monitoring (MRM) assays to identify biomarkers. Of the 38 protein groups discovered by iTRAQ, 18 already had existing MRM assays. Based on MRM, we identified an eight-protein biomarker panel (22 kDa protein, afamin, α1 antichymotrypsin, apolipoprotein E, β-Ala His dipeptidase, haemoglobin α-2, isoform 1 of sex hormone-binding globulin, and peroxiredoxin 2) that was very specific and sensitive for male AFD patients. In female AFD patients, we identified a nine-marker panel of proteins with only three proteins, apolipoprotein E, haemoglobin α-2, and peroxiredoxin 2, common to both genders, suggesting a gender-specific alteration in plasma biomarkers in patients with AFD. The biomarkers were validated in plasma samples from 48 subjects using MRM, and they performed inferiorly in patients with heart failure.Conclusions We have identified gender-specific plasma protein biomarker panels that are specific and sensitive for the AFD phenotype. The gender-specific panels offer important insight into potential differences in pathophysiology and prognosis between males and females with AFD.
    European Journal of Heart Failure 01/2015; 17(3). DOI:10.1002/ejhf.230 · 6.53 Impact Factor

  • ESC Heart Failure 01/2015; 30(10):n/a-n/a. DOI:10.1002/ehf2.12076
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    ABSTRACT: Abstract Multi-omics research is a key ingredient of data-intensive life sciences research, permitting measurement of biological molecules at different functional levels in the same individual. For a complete picture at the biological systems level, appropriate statistical techniques must however be developed to integrate different 'omics' data sets (e.g., genomics and proteomics). We report here multivariate projection-based analyses approaches to genomics and proteomics data sets, using the case study of and applications to observations in kidney transplant patients who experienced an acute rejection event (n=20) versus non-rejecting controls (n=20). In this data sets, we show how these novel methodologies might serve as promising tools for dimension reduction and selection of relevant features for different analytical frameworks. Unsupervised analyses highlighted the importance of post transplant time-of-rejection, while supervised analyses identified gene and protein signatures that together predicted rejection status with little time effect. The selected genes are part of biological pathways that are representative of immune responses. Gene enrichment profiles revealed increases in innate immune responses and neutrophil activities and a depletion of T lymphocyte related processes in rejection samples as compared to controls. In all, this article offers candidate biomarkers for future detection and monitoring of acute kidney transplant rejection, as well as ways forward for methodological advances to better harness multi-omics data sets.
    Omics A Journal of Integrative Biology 11/2014; 18(11):682-95. DOI:10.1089/omi.2014.0062 · 2.36 Impact Factor
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    ABSTRACT: Leiomyosarcoma (LMS) is a mesenchymal cancer that occurs throughout the body. Although LMS is easily recognized histopathologically, the cause of the disease remains unknown. Versican, an extracellular matrix (ECM) proteoglycan, increases in LMS. Microarray analyses of 80 LMS and 24 leiomyomas show a significant elevated expression of versican in human LMS vs. benign leiomyomas. To explore the importance of versican in this smooth muscle cell tumor, we used versican-directed siRNA to knockdown versican expression in a LMS human cell line, SK-LMS-1. Decreased versican expression was accompanied by slower rates of LMS cell proliferation and migration, increased adhesion, and decreased accumulation of the ECM macromolecule hyaluronan. Addition of purified versican to cells expressing versican siRNA restored cell proliferation to the level of LMS controls, increased the pericellular coat and the retention of hyaluronan, and decreased cell adhesion in a dose-dependent manner. The presence of versican was not only synergistic with hyaluronan in increasing cell proliferation, but the depletion of versican decreased hyaluronan synthase expression and decreased the retention of hyaluronan. When LMS cells stably expressing versican siRNA were injected into nude mice, the resulting tumors displayed significantly less versican and hyaluronan staining, had lower volumes, and reduced levels of mitosis as compared to controls. Collectively, these results suggest a role for using versican as a point of control in the management and treatment of LMS.
    Journal of Biological Chemistry 10/2014; 289(49). DOI:10.1074/jbc.M114.607168 · 4.57 Impact Factor

  • Journal of Cardiac Failure 08/2014; 20(8S):S28. DOI:10.1016/j.cardfail.2014.06.081 · 3.05 Impact Factor
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    Soroush Samadian · Bruce McManus · Mark Wilkinson ·
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    ABSTRACT: Background Measurement-unit conflicts are a perennial problem in integrative research domains such as clinical meta-analysis. As multi-national collaborations grow, as new measurement instruments appear, and as Linked Open Data infrastructures become increasingly pervasive, the number of such conflicts will similarly increase. Methods We propose a generic approach to the problem of (a) encoding measurement units in datasets in a machine-readable manner, (b) detecting when a dataset contained mixtures of measurement units, and (c) automatically converting any conflicting units into a desired unit, as defined for a given study. Results We utilized existing ontologies and standards for scientific data representation, measurement unit definition, and data manipulation to build a simple and flexible Semantic Web Service-based approach to measurement-unit harmonization. A cardiovascular patient cohort in which clinical measurements were recorded in a number of different units (e.g., mmHg and cmHg for blood pressure) was automatically classified into a number of clinical phenotypes, semantically defined using different measurement units. Conclusions We demonstrate that through a combination of semantic standards and frameworks, unit integration problems can be automatically detected and resolved.
    BMC Medical Genomics 05/2014; 7(Suppl 1):S12. DOI:10.1186/1755-8794-7-S1-S12 · 2.87 Impact Factor
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    Dataset: nm.3508-S1

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    Dataset: nm.3508-S2

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    ABSTRACT: Chronic heart failure is a costly epidemic that affects up to 2% of people in developed countries. The purpose of this study was to discover novel blood proteomic biomarker signatures of recovered heart function that could lead to more effective heart failure patient management by both primary care and specialty physicians. The discovery cohort included 41 heart transplant patients and 20 healthy individuals. Plasma levels of 138 proteins were detected in at least 75% of these subjects by iTRAQ mass spectrometry. Eighteen proteins were identified that had (i) differential levels between pre-transplant patients with end-stage heart failure and healthy individuals; and (ii) levels that returned to normal by 1 month post-transplant in patients with stable heart function after transplantation. Seventeen of the 18 markers were validated by multiple reaction monitoring mass spectrometry in a cohort of 39 heart failure patients treated with drug therapy, of which 30 had recovered heart function and 9 had not. This 17-protein biomarker panel had 93% sensitivity and 89% specificity, while the RAMP® NT-proBNP assay had the same specificity but 80% sensitivity. Performance further improved when the panel was combined with NT-proBNP, yielding a net reclassification index relative to NT-proBNP of 0.28. We have identified potential blood biomarkers of recovered heart function by harnessing data from transplant patients. These biomarkers can lead to the development of an inexpensive protein-based blood test that could be used by physicians to monitor response to therapy in heart failure, resulting in more personalized, front-line heart failure patient management.
    European Journal of Heart Failure 05/2014; 16(5). DOI:10.1002/ejhf.65 · 6.53 Impact Factor
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    ABSTRACT: Interferon-α (IFN-α) is essential for antiviral immunity, but in the absence of matrix metalloproteinase-12 (MMP-12) or IκBα (encoded by NFKBIA) we show that IFN-α is retained in the cytosol of virus-infected cells and is not secreted. Our findings suggest that activated IκBα mediates the export of IFN-α from virus-infected cells and that the inability of cells in Mmp12(-/-) but not wild-type mice to express IκBα and thus export IFN-α makes coxsackievirus type B3 infection lethal and renders respiratory syncytial virus more pathogenic. We show here that after macrophage secretion, MMP-12 is transported into virus-infected cells. In HeLa cells MMP-12 is also translocated to the nucleus, where it binds to the NFKBIA promoter, driving transcription. We also identified dual-regulated substrates that are repressed both by MMP-12 binding to the substrate's gene exons and by MMP-12-mediated cleavage of the substrate protein itself. Whereas intracellular MMP-12 mediates NFKBIA transcription, leading to IFN-α secretion and host protection, extracellular MMP-12 cleaves off the IFN-α receptor 2 binding site of systemic IFN-α, preventing an unchecked immune response. Consistent with an unexpected role for MMP-12 in clearing systemic IFN-α, treatment of coxsackievirus type B3-infected wild-type mice with a membrane-impermeable MMP-12 inhibitor elevates systemic IFN-α levels and reduces viral replication in pancreas while sparing intracellular MMP-12. These findings suggest that inhibiting extracellular MMP-12 could be a new avenue for the development of antiviral treatments.
    Nature medicine 04/2014; 20(5). DOI:10.1038/nm.3508 · 27.36 Impact Factor
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    ABSTRACT: Acute rejection is a major complication of solid organ transplantation that prevents the long-term assimilation of the allograft. Various populations of lymphocytes are principal mediators of this process, infiltrating graft tissues and driving cell-mediated cytotoxicity. Understanding the lymphocyte-specific biology associated with rejection is therefore critical. Measuring genome-wide changes in transcript abundance in peripheral whole blood cells can deliver a comprehensive view of the status of the immune system. The heterogeneous nature of the tissue significantly affects the sensitivity and interpretability of traditional analyses, however. Experimental separation of cell types is an obvious solution, but is often impractical and, more worrying, may affect expression, leading to spurious results. Statistical deconvolution of the cell type-specific signal is an attractive alternative, but existing approaches still present some challenges, particularly in a clinical research setting. Obtaining time-matched sample composition to biologically interesting, phenotypically homogeneous cell sub-populations is costly and adds significant complexity to study design. We used a two-stage, in silico deconvolution approach that first predicts sample composition to biologically meaningful and homogeneous leukocyte sub-populations, and then performs cell type-specific differential expression analysis in these same sub-populations, from peripheral whole blood expression data. We applied this approach to a peripheral whole blood expression study of kidney allograft rejection. The patterns of differential composition uncovered are consistent with previous studies carried out using flow cytometry and provide a relevant biological context when interpreting cell type-specific differential expression results. We identified cell type-specific differential expression in a variety of leukocyte sub-populations at the time of rejection. The tissue-specificity of these differentially expressed probe-set lists is consistent with the originating tissue and their functional enrichment consistent with allograft rejection. Finally, we demonstrate that the strategy described here can be used to derive useful hypotheses by validating a cell type-specific ratio in an independent cohort using the nanoString nCounter assay.
    PLoS ONE 04/2014; 9(4):e95224. DOI:10.1371/journal.pone.0095224 · 3.23 Impact Factor

Publication Stats

8k Citations
1,455.91 Total Impact Points


  • 2009-2015
    • Centre of Excellence for the Prevention of Organ Failure (PROOF)
      Vancouver, British Columbia, Canada
  • 1995-2015
    • University of British Columbia - Vancouver
      • • Department of Pathology and Laboratory Medicine
      • • Department of Medical Genetics
      Vancouver, British Columbia, Canada
  • 2002-2014
    • UBC - Universidade BRAZ CUBAS
  • 1998-2014
    • St. Paul's Hospital
      Saskatoon, Saskatchewan, Canada
    • Gunma University
      • Department of Clinical Laboratory Medicine
      Maebashi-shi, Gunma-ken, Japan
  • 2012
    • Dalhousie University
      Halifax, Nova Scotia, Canada
  • 2004-2007
    • Providence Health Care
      Vancouver, British Columbia, Canada
    • University of Virginia
      Charlottesville, Virginia, United States
    • University of Southern California
      Los Angeles, California, United States
  • 2005-2006
    • University of Manitoba
      • Department of Surgery
      Winnipeg, Manitoba, Canada
    • Complutense University of Madrid
      Madrid, Madrid, Spain
  • 2003
    • University of Washington Seattle
      • Department of Pathology
      Seattle, Washington, United States
    • Aarhus University
      • Department of Zoophysiology
      Aarhus, Central Jutland, Denmark
  • 2001
    • Université de Technologie de Compiègne
      Compiègne, Picardie, France
  • 1997
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
  • 1984-1996
    • University of Nebraska Medical Center
      • • Division of Pediatric Cardiology
      • • Department of Pathology and Microbiology
      • • Department of Internal Medicine
      Omaha, Nebraska, United States
  • 1984-1992
    • University of Nebraska at Omaha
      • • Department of Pathology and Microbiology
      • • Department of Pediatrics
      Omaha, Nebraska, United States