Thomas J Podor

St. Paul's Hospital, Saskatoon, Saskatchewan, Canada

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Publications (20)64.45 Total impact

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    ABSTRACT: Vitronectin (VN) is an abundant acute-phase plasma protein that regulates cell adhesion and migration as well as interactions with components of the plasminogen activator/plasmin system, specifically plasminogen activator inhibitor type 1. This system plays a major role in tissue remodelling regulating wound healing after myocardial infarction. To investigate the feasibility of using VN knockout mice (VN(-/-)) to study the role of VN on ventricular remodelling following myocardial infarction. Specifically bred VN(-/-) mice and normal wild-type (VN(+/+)) mice underwent coronary artery ligation and were assessed 28 days postligation using echocardiography and morphometric histology. No difference was observed between VN(-/-) mice and VN(+/+) mice with respect to gross phenotype, weight, coronary anatomy or echocardiographically measured ejection fraction (56%). Following myocardial infarction, VN(-/-) mice exhibited less ventricular dilation and less impairment in echocardiographic ejection fraction compared with VN(+/+) mice (48% versus 41%; P=0.01). VN(-/-) mice also exhibited smaller infarcts on morphometric analysis. The results of the present study confirmed the feasibility of using coronary artery ligation in VN knockout mice to investigate the role of VN in post-myocardial infarction remodelling. The absence of VN appears to result in favourable effects on wound healing. These data suggest that this model may offer novel insights into the role of VN in the regulation of myocardial remodelling.
    Experimental and clinical cardiology 01/2013; 18(1):43-47. · 0.76 Impact Factor
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    ABSTRACT: Platelet microparticles (PMPs) are a promising prognostic marker for thrombotic disorders because of their release during platelet activation. The use of flow cytometry for the enumeration of PMPs in plasma has generated controversy due to their size, which is below the stated detection limits of conventional flow cytometry instruments. The potential impact of this is an underestimation of PMP counts. To address this possibility, we used a combination of fluorescence-activated cell sorting (FACS) and atomic force microscopy (AFM) to determine the size distribution of PMPs present in plasma from acute myocardial infarction (AMI) patients and normal volunteers, and PMPs generated by expired platelet concentrates and washed platelets treated with agonists such as thrombin and calcium ionophore (A23187). According to AFM image analysis, there was no statistically significant difference in height or volume distributions in PMPs from thrombin-activated, calcium ionophore-activated, expired platelet concentrates and plasma from healthy volunteers and AMI patients. Based on volume, expired platelets released the greatest proportion of exosomes (< 1.0 × 10(-22) L(3) in volume) in relation to the entire PMP population (29.7%) and the smallest proportion of exosomes was observed in AMI patient plasma (1.8%). Moreover, AFM imaging revealed that PMPs from expired platelets exhibited smooth surfaces compared with other PMP types but this was not statistically significant. We confirm that flow cytometry is capable of analyzing PMPs from plasma by using AFM to perform nanoscale measurements of individual PMP events isolated by FACS. This method also provided the first quantitative nanoscale images of PMP ultrastructure.
    Journal of Thrombosis and Haemostasis 12/2011; 9(12):2466-76. DOI:10.1111/j.1538-7836.2011.04528.x · 5.55 Impact Factor
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    ABSTRACT: Granulocyte-colony stimulating factor (G-CSF) mobilizes progenitors from the bone marrow (BM) and into the circulation. In cardiac transplantation, G-CSF pretreatment of both donors and recipients has been found to improve cardiac function. The aim of this study was to examine whether the observed benefit of G-CSF pretreatment in cardiac transplantation involves vascular repopulation by host progenitor cells. Progenitor cells were exposed to immunosuppressive agents±G-CSF. The effect of drug treatment on total cell counts, proliferation, angiogenesis, apoptosis, and tubule formation was assessed. C57BL/6BM-GFP chimeric recipients underwent cardiac transplantation. Host progenitor cell seeding was evaluated on hearts 14 and 30 days post-transplant. G-CSF treatment of BM-derived progenitor cells in vitro improved survival, proliferation, and angiogenesis of the cells despite treatment with immunosuppressive agents. G-CSF pretreatment of BM-GFP transgenic recipient mice prior to heart transplantation resulted in increased re-endothelialization at 30 days post-transplant in G-CSF pretreated allografts (9.3±2.2%) relative to nonpretreated allografts (3.4±1.6%). G-CSF pretreated allografts also demonstrated a reduction of intimal narrowing in vessels of the transplanted heart. These findings suggest that G-CSF pretreatment leads to elevated numbers of host progenitor cells which may contribute to reconstitution of damaged allograft blood vessels.
    Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology 02/2009; 19(1):36-47. DOI:10.1016/j.carpath.2008.10.007 · 2.34 Impact Factor
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    ABSTRACT: Anti-vimentin antibodies (AVA) are associated with autoimmunity and solid organ transplantation, conditions associated with vascular disease, but their contribution to disease pathogenesis is unknown. Here, we have examined interactions between AVA (mAb and serum from patients) and various leukocyte populations using whole blood and flow cytometry. Normal blood treated with patient sera containing high AVA-IgM titers or with a vimentin-specific monoclonal IgM led to activation of platelets and other leukocytes, as demonstrated by induced expression of P-selectin, fibrinogen, tissue factor, and formation of platelet:leukocyte (P:L) conjugates and a reduction in platelet counts. This activity was antigen (vimentin)-specific and was not mediated by irrelevant IgM antibodies. Flow cytometry demonstrated that AVA do not bind directly to resting platelets in whole blood, but they bind to approximately 10% of leukocytes. Supernatant, derived from AVA-treated leukocytes, induced platelet activation, as measured by the generation of platelet microparticles, when added to platelet-rich plasma. When AVA were added to whole blood in the presence of CV-6209, a platelet-activating factor (PAF) receptor inhibitor, platelet depletion was inhibited. This suggests that PAF is one of the mediators released from AVA-activated leukocytes that leads to P:L conjugation formation and platelet activation. In summary, AVA bind to leukocytes, resulting in release of a PAF and prothrombotic factor that exert a paracrine-activating effect on platelets. Overall, this proposed mechanism may explain the pathogenesis of thrombotic events in autoimmune diseases associated with AVA.
    Journal of Leukocyte Biology 03/2008; 83(2):263-71. DOI:10.1189/jlb.0607339 · 4.30 Impact Factor
  • The Journal of Heart and Lung Transplantation 02/2007; 26(2). DOI:10.1016/j.healun.2006.11.399 · 5.61 Impact Factor
  • Thrombosis and Haemostasis 01/2007; 96(6):859-61. DOI:10.1160/TH06-03-0180 · 5.76 Impact Factor
  • Vascular Pharmacology 09/2006; 45(3). DOI:10.1016/j.vph.2006.08.124 · 4.62 Impact Factor
  • Journal of Cardiac Failure 08/2006; 12(6). DOI:10.1016/j.cardfail.2006.06.094 · 3.07 Impact Factor
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    ABSTRACT: Signaling through the insulin-like growth factor I receptor (IGF-IR) axis is essential for transformation by many dominantly acting oncoproteins. However, the mechanism by which IGF-IR contributes to oncogenesis remains unknown. To examine this, we compared transformation properties of the oncogenic ETV6-NTRK3 (EN) chimeric tyrosine kinase in IGF-IR-null R- mouse embryo fibroblasts with R- cells engineered to reexpress IGF-IR (R+ cells). We previously showed that R- cells expressing EN (R- EN cells) are resistant to transformation but that transformation is restored in R+ cells. We now show that while R- EN cells have intact Ras-extracellular signal-regulated kinase signaling and cell cycle progression, they are defective in phosphatidylinositol-3-kinase (PI3K)-Akt activation and undergo detachment-induced apoptosis (anoikis) under anchorage-independent conditions. In contrast, R+ cells expressing EN (R+ EN cells) suppress anoikis and are fully transformed. The requirement for IGF-IR in R- EN cells is overcome by ectopic expression of either activated Akt or a membrane-targeted form of EN. Moreover, compared to R- EN cells, R+ EN cells show a dramatic increase in membrane localization of insulin receptor substrate 1 (IRS-1) in association with EN. Since EN is known to bind IRS-1 as an adaptor protein, our findings suggest that IGF-IR may function to localize EN/IRS-1 complexes to cell membranes, in turn facilitating PI3K-Akt activation and suppression of anoikis.
    Molecular and Cellular Biology 04/2006; 26(5):1754-69. DOI:10.1128/MCB.26.5.1754-1769.2006 · 5.04 Impact Factor
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    ABSTRACT: An abstract is unavailable. This article is available as HTML full text and PDF.
    Journal of Investigative Medicine 12/2005; 54(1):S123-S124. · 1.50 Impact Factor
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    ABSTRACT: Currently, there is intense debate regarding the origin of reparative cells in injured hearts and vasculature. To determine the contribution of recipient bone marrow (BM)-derived cells to the regeneration of cells in the vasculature of transplanted hearts and to examine the effect of immunosuppression on this phenomenon, we evaluated the fate of green fluorescent protein (GFP)-positive recipient BM cells in non-GFP-expressing cardiac allografts. C57BL/6 BM-GFP chimeric recipients underwent cardiac transplantation. Allografts were immunosuppressed with tacrolimus for 14 or 30 days post-transplantation or were saline treated. Hearts were excised and stained with markers for endothelial cells (EC) or smooth muscle cells (SMC). Colocalization with BM-derived recipient cells was evaluated using confocal microscopy with three-dimensional image analysis. Immunosuppression with tacrolimus did not affect the frequency of recipient BM-derived cell chimerism as EC or SMC phenotypes. A higher frequency of EC chimerism was found at 14 days as compared to 30 days post-transplantation in allograft hearts. BM-derived recipient cells are recruited to areas of donor vascular injury with intercalation of recipient EC and SMC in the setting of ongoing alloimmune recognition of the allograft. Our findings confirm that immunosuppression with tacrolimus does not affect the frequency of recipient BM-derived cell repopulation at an early time point 14 days post-transplantation. EC repopulation by BM-derived recipient cells was found to be an early event in transplanted allograft hearts, which decreased in frequency over time.
    Laboratory Investigation 09/2005; 85(8):982-91. DOI:10.1038/labinvest.3700302 · 3.83 Impact Factor
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    ABSTRACT: Currently, the tenet that heart muscle cells are terminally differentiated and incapable of self-repair is being challenged. Recent experimental observations suggest that both endogenous and exogenous stem cell populations have the potential to regenerate damaged areas within the heart. These findings hold promise for new therapeutic strategies to treat cardiovascular diseases, including common conditions like myocardial infarction and transplant vascular disease (TVD). In this chapter, we focus on the study of endogenous stem cells in the context of their role in modulation of cardiovascular diseases, including ischemic heart disease and TVD. Specific experimental models and methods used to study the phenomena of endogenous bone marrow-derived stem cell migration and potential differentiation are also described.
    Methods in molecular medicine 02/2005; 112:223-38.
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    ABSTRACT: The use of specialized reporter genes to monitor real-time, tissue-specific transgene expression in animal models offers an opportunity to circumvent current limitations associated with the establishment of transgenic mouse models. The Cre-loxP and the tetracycline (Tet)-inducible systems are useful methods of conditional gene expression that allow spatial (cell-type-specific) and temporal (inducer-dependent) control. Most often, the alpha-myosin heavy chain (alpha-MHC) promoter is used in these inducible systems to restrict expression of reporter genes and transgenes to the myocardium. An overview of each inducible system is described, along with suggested reporter genes for real-time, noninvasive imaging in the myocardium. Effective gene delivery of the inducible gene expression system is carried out by lentiviral vectors, which offer high transduction efficiency, long-term transgene expression, and low immunogenicity. This chapter outlines the packaging of myocardium-specific inducible expression systems into lentiviral vectors, in which a transgene and a reporter gene are transduced into cardiomyocytes. In doing so, transgene and reporter expression can be monitored/tracked with bioluminescence imaging (BLI) and positron emission tomography (PET).
    Methods in molecular medicine 02/2005; 112:109-54.
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    ABSTRACT: T cell-induced cytotoxicity, of which granzyme B is a key mediator, is believed to contribute to the pathogenesis of inflammatory vascular diseases. In this report, we investigate the mechanism of granzyme B-induced smooth muscle cell (SMC) death. The addition of purified granzyme B alone to cultured SMCs caused a significant reduction in cell viability. Chromatin condensation, phosphatidylserine externalization, and membrane blebbing were observed, indicating that the mechanism of granzyme B-induced SMC death was through apoptosis. Activated splenocytes from perforin-knockout mice induced SMC death through a granzyme B-mediated pathway. Inhibition of the proteolytic activities of caspases and granzyme B prevented granzyme B-induced SMC death, whereas attenuation of granzyme B internalization with mannose-6-phosphate (M6P) did not. Further, granzyme B induced the cleavage of several SMC extracellular proteins, including fibronectin, and reduced focal adhesion kinase phosphorylation. These results indicate that granzyme B can induce apoptosis of SMCs in the absence of perforin by cleaving extracellular proteins, such as fibronectin.
    Arteriosclerosis Thrombosis and Vascular Biology 01/2005; 24(12):2245-50. DOI:10.1161/01.ATV.0000147162.51930.b7 · 5.53 Impact Factor
  • Cardiovascular Pathology 05/2004; 13(3):172-172. DOI:10.1016/j.carpath.2004.03.516 · 2.34 Impact Factor
  • Cardiovascular Pathology 05/2004; 13(3):142-143. DOI:10.1016/j.carpath.2004.03.428 · 2.34 Impact Factor
  • Hon Sing Leong, Thomas J Podor
    Cardiovascular Pathology 05/2004; 13(3):175-175. DOI:10.1016/j.carpath.2004.03.526 · 2.34 Impact Factor
  • Nana Rezai, Thomas J Podor, Bruce M McManus
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    ABSTRACT: Adult bone marrow-derived stem/progenitor cells have traditionally been considered to be tissue-specific cells with limited capacity for differentiation. However, recent discoveries have generated tremendous excitement regarding possible applications of stem cells, particularly bone marrow-derived stem cells, in the treatment of human diseases. The potential ability to regenerate cells of various different lineages has raised the therapeutic possibility of using these bone marrow-derived stem cells as a source of cells for tissue repair and regeneration. Tissue engineering is a rapidly expanding interdisciplinary field aimed at restoring function to tissues through the delivery of constructs which become integrated into the patient. The use of bone marrow-derived stem cells provides a less invasive source for cells applicable to tissue engineering, including cardiovascular tissues such as heart valves, blood vessels, and myocardium. Although these strategies are in the early stages of development, they are conceptually promising and offer important insights into the future treatment of various cardiovascular ailments.
    Artificial Organs 03/2004; 28(2):142-51. DOI:10.1111/j.1525-1594.2004.47334.x · 1.87 Impact Factor
  • The Journal of Heart and Lung Transplantation 02/2004; 23(2). DOI:10.1016/j.healun.2003.11.244 · 5.61 Impact Factor
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    ABSTRACT: Atheromatous diseases are lipid and cell-rich vascular disorders that include coronary artery disease (CAD), transplant vascular disease (TVD), and restenosis. Considering the inflammatory nature of these diseases, cytotoxic immune mechanisms such as the FasL and granzyme/perforin pathways most likely play important roles in the development and remodeling of many lesions. Furthermore, although the contributions of immune responses to each disease vary, the correspondent localization of certain mediators and effectors suggests that they may contribute to a spectrum of atheromatous diseases. In this review, the contribution of immune cell-mediated cell death in the onset and pathogenesis of CAD and TVD is examined.
    Cardiovascular Toxicology 02/2003; 3(3):269-82. DOI:10.1385/CT:3:3:269 · 2.06 Impact Factor

Publication Stats

256 Citations
64.45 Total Impact Points


  • 2011–2013
    • St. Paul's Hospital
      Saskatoon, Saskatchewan, Canada
  • 2003–2009
    • University of British Columbia - Vancouver
      • Department of Pathology and Laboratory Medicine
      Vancouver, British Columbia, Canada
  • 2007
    • University of Toronto
      • Department of Medicine
      Toronto, Ontario, Canada