Philip A Marsden

University of Toronto, Toronto, Ontario, Canada

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Publications (139)1041.58 Total impact

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    ABSTRACT: Binding of the receptor CXCR4 to its ligand SDF-1 promotes cell survival and is under the influence of a number of regulatory processes including enzymatic ligand inactivation by endopeptidases such as matrix metalloproteinase-9 (MMP-9). In light of the pivotal role that the SDF-1/CXCR4 axis plays in renal development and in the pathological growth of renal cells, we explored the function of this pathway in diabetic rats and in biopsies from patients with diabetic nephropathy, hypothesizing that the pro-survival effects of CXCR4 in resident cells would attenuate renal injury. Renal CXCR4 expression was observed to be increased in diabetic rats, whereas antagonism of the receptor unmasked albuminuria and accelerated tubular epithelial cell death. In cultured cells, CXCR4 blockade promoted tubular cell apoptosis, upregulated Bcl-2-associated death promoter and prevented high glucose/SDF-1 augmented phosphorylation of the pro-survival kinase, Akt. Although CXCR4 expression was also increased in biopsy tissue from patients with diabetic nephropathy serine 339 phosphorylation of the receptor, indicative of ligand-engagement, was unaffected. Coincident with these changes in receptor expression but not activity, MMP-9 was also upregulated in diabetic nephropathy biopsies. Supporting a ligand-inactivating effect of the endopeptidase, exposure of cultured cells to recombinant MMP-9 abrogated SDF-1 induced Akt phosphorylation. These observations demonstrate a potentially reno-protective role for CXCR4 in diabetes that is impeded in its actions in the human kidney by the coincident upregulation of ligand-inactivating endopeptidases. Therapeutically intervening in this interplay may limit tubulointerstitial injury, the principal determinant of renal decline in diabetes.
    Endocrinology 12/2014; · 4.72 Impact Factor
  • Marisa Battistella, Philip A Marsden
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    ABSTRACT: The discovery of RNA interference (RNAi) holds the potential to alter the paradigm of medical therapeutics. With the ability to selectively silence the function of a gene, RNAi not only provides an indispensable research tool for determining the function of a gene, but also offers potential for the development of novel therapeutics that will inhibit specific genes involved in disease. New concepts in therapeutics have been uncovered through the study of RNAi. Nuances have emerged. For instance, global RNAi pathways can be affected by somatic mutations in cancer and cellular stress, such as hypoxia. Also, viral gene therapy can have unexpected effects on endogenous short noncoding RNA pathways. Therefore, it is important to understand where RNAi therapeutics enter the processing pathways. We highlight the evolving use of RNAi as a new class of therapeutics, such as for amyloidosis, and address some of the anticipated challenges associated with its clinical application. This article is protected by copyright. All rights reserved.
    Clinical Pharmacology &#38 Therapeutics 11/2014; · 6.85 Impact Factor
  • Myron I Cybulsky, Philip A Marsden
    Arteriosclerosis Thrombosis and Vascular Biology 09/2014; 34(9):1806-8. · 5.53 Impact Factor
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    ABSTRACT: Tissue hypoxia likely contributes to anemia-induced organ injury and mortality. Severe anemia activates hypoxia-inducible factor (HIF) signaling by hypoxic- and neuronal nitric oxide synthase- (nNOS) dependent mechanisms. However, organ-specific hemoglobin (Hb) thresholds for increased HIF expression have not been defined. To assess organ specific Hb thresholds for tissue hypoxia, HIF-α (ODD) luciferase mice were hemodiluted to mild, moderate, or severe anemia corresponding to Hb levels of 90, 70, and 50g/L, respectively. HIF luciferase reporter activity, HIF protein, and HIF-dependent RNA levels were assessed. In the brain, HIF-1α was paradoxically decreased at mild anemia, returned to baseline at moderate anemia, and then increased at severe anemia. Brain HIF-2α remained unchanged at all Hb levels. Both kidney HIF-1α and -2α increased earlier (Hb~70-90g/L) in response to anemia. Liver also exhibited an early HIF-1α response. Carotid blood flow was increased early (Hb~70g/L) but renal blood flow remained relatively constant, only increased at Hb of 50g/L. Anemia increased nNOS (brain and kidney) and eNOS (kidney) levels. Whereas anemia-induced increases in brain HIFα were nNOS-dependent, our current data demonstrate that increased renal HIFα was nNOS-independent. HIF-dependent RNA levels increased linearly (~10 fold) in the brain. However, renal HIF-RNA responses (MCT4, EPO) increased exponentially (~100 fold). Plasma EPO levels increased near Hb threshold of 90g/L, suggesting that the EPO response is sensitive. Collectively, these observations suggest that each organ expresses a different threshold for cellular HIF/NOS hypoxia responses. This knowledge may help define the mechanism(s) by which the brain and kidney maintain oxygen homeostasis during anemia.
    AJP Regulatory Integrative and Comparative Physiology 04/2014; · 3.28 Impact Factor
  • Paul J Turgeon, Aravin N Sukumar, Philip A Marsden
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    ABSTRACT: Genome-wide association studies (GWAS) have become a powerful tool in the identification of disease-associated variants. Unfortunately, many of these studies have found that the estimated variability in cardiovascular disease risk cannot be fully explained by traditional paradigms of genetic variation in protein coding genes. Moreover, traditional views do not sufficiently explain the well-known link between cardiovascular disease and environmental influence. We posit that epigenetics, defined as chromatin-based mechanisms important in the regulation of gene expression that do not involve changes in the DNA sequence per se, represents the missing link. The nuclear-based mechanisms that contribute to epigenetic gene regulation can be broadly separated into three unique but highly interrelated processes: DNA methylation and hydroxymethylation; histone density and post-translational modifications; and RNA-based mechanisms. Together they complement the cis/trans perspective on transcriptional control paradigms in blood vessels. Moreover, it provides a molecular basis for understanding how the environment impacts the genome to modify cardiovascular disease risk over the lifetime of a cell and its offspring. This review provides an introduction to epigenetic function and cardiovascular disease, with a focus on endothelial cell biology. Additionally, we highlight emerging concepts on epigenetic gene regulation that are highly relevant to atherosclerosis and coronary artery disease.
    Medical epigenetics. 04/2014; 2(1):37-52.
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    ABSTRACT: The progressive decline of renal function in chronic kidney disease (CKD) is characterized by both disruption of the microvascular architecture and the accumulation of fibrotic matrix. One angiogenic pathway recently identified as playing an essential role in renal vascular development is the stromal cell-derived factor-1α (SDF-1)/CXCR4 pathway. Because similar developmental processes may be recapitulated in the disease setting, we hypothesized that the SDF-1/CXCR4 system would regulate microvascular health in CKD. Expression of CXCR4 was observed to be increased in the kidneys of subtotally nephrectomized (SNx) rats and in biopsies from patients with secondary focal segmental glomerulosclerosis (FSGS), a rodent model and human correlate both characterized by aberration of the renal microvessels. A reno-protective role for local SDF-1/CXCR4 signaling was indicated by i) CXCR4-dependent glomerular eNOS activation following acute SDF-1 administration; and ii) acceleration of renal function decline, capillary loss and fibrosis in SNx rats treated with chronic CXCR4 blockade. In contrast to the upregulation of CXCR4, SDF-1 transcript levels were decreased in SNx rat kidneys as well as in renal fibroblasts exposed to the pro-fibrotic cytokine transforming growth factor β (TGF-β), the latter effect being attenuated by histone deacetylase inhibition. Increased renal SDF-1 expression was, however, observed following the treatment of SNx rats with the ACE inhibitor, perindopril. Collectively, these observations indicate that local SDF-1/CXCR4 signaling functions to preserve microvascular integrity and prevent renal fibrosis. Augmentation of this pathway, either purposefully or serendipitously with either novel or existing therapies, may attenuate renal decline in CKD.
    PLoS ONE 03/2014; 9(3):e92227. · 3.53 Impact Factor
  • H S Jeffrey Man, Albert K Y Tsui, Philip A Marsden
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    ABSTRACT: Nitric oxide (NO) production is catalyzed by three distinct enzymes, namely, neuronal nitric oxide synthase (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). The production of NO by vascular endothelium relies mainly on eNOS. Curiously, iNOS and nNOS also are relevant for vascular NO production in certain settings. By relaxing vascular smooth muscle, the classical view is that NO participates in O2 homeostasis by increasing local blood flow and O2 delivery. It is now appreciated that NO has an even more fundamental role in cellular oxygen sensing at the cellular and physiological level. A key component of cellular oxygen sensing is the hypoxia-inducible factor (HIF) that activates a transcriptional program to promote cellular survival under conditions of inadequate oxygen supply. Important new insights demonstrate that HIF protein is stabilized by two parallel pathways: (1) a decrease in the O2-dependent prolyl hydroxylation of HIF and (2) NO-dependent S-nitrosylation of HIF pathway components including HIF-α. The need for these two complementary pathways to HIF activation arises because decreased oxygen delivery can occur not only by decreased ambient oxygen but also by decreased blood oxygen-carrying capacity, as with anemia. In turn, NO production is tightly linked to O2 homeostasis. O2 is a key substrate for the generation of NO and impacts the enzymatic activity and expression of the enzymes that catalyze the production of NO, the nitric oxide synthases. These relationships manifest in a variety of clinical settings ranging from the unique situation of humans living in hypoxic environments at high altitudes to the common scenario of anemia and the use of therapeutics that can bind or release NO.
    Vitamins & Hormones 01/2014; 96:161-92. · 1.78 Impact Factor
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    J J David Ho, Philip A Marsden
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    ABSTRACT: Posttranscriptional regulation of mRNA species represents a major regulatory checkpoint in the control of gene expression. Historically, RNA-binding proteins (RBPs) have been regarded as the primary regulators of mRNA stability and translation. More recently, however, microRNAs have emerged as a class of potent and pervasive posttranscriptional rheostats that similarly affect mRNA stability and translation. The observation that both microRNAs and RBPs regulate mRNA stability and translation has initiated a newer area of research that involves the examination of dynamic interactions between these two important classes of posttranscriptional regulators, the myriad of factors that influence these biological interactions, and ultimately, their effects on target mRNAs. Specifically, microRNAs and RBPs can act synergistically to effect mRNA destabilization and translational inhibition. They can also engage in competition with each other and exert opposing effects on target mRNAs. To date, several key studies have provided critical details regarding the mechanisms and principles of interaction between these molecules. Additionally, these findings raise important questions regarding the regulation of these interactions, including the roles of posttranslational modification, subcellular localization, target inhibition versus activation, and changes in expression levels of these regulatory factors, especially under stimulus- and cell-specific conditions. Indeed, further experimentation is warranted to address these key issues that pertain to the collaboration and competition between microRNAs and RBPs. Significantly, the elucidation of these important details bears critical implications for disease management, especially for those diseases in which these cellular factors are dysregulated. For further resources related to this article, please visit the WIREs website. Conflict of interest: We declare that there are no financial or other conflicts of interest related to this work.
    WIREs RNA 10/2013; · 6.15 Impact Factor
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    ABSTRACT: Shiga toxin-producing E. coli represents a significant global health concern, especially as hypervirulent pathogens surface amidst outbreaks of hemolytic uremic syndrome (HUS). Shiga toxin (Stx) is key in the microangiopathic events underlying the disease and its central role is underscored by the unprecedented HUS outbreak in Germany in 2011. The mechanisms of Stx-mediated endothelial dysfunction have been a major focus of research that has contributed to the current understanding of the pathogenic changes in endothelial phenotype leading to HUS. Among the newer concepts are Stx-mediated gene regulation in the absence of protein synthesis inhibition, a potential role for complement activation, and accumulating evidence for detectable serum markers before the onset of the classic clinical features of HUS. Further investigation of newer therapeutic targets and potential prognostic markers is essential to assess their utility in mitigating disease and/or predicting outcomes and will provide an improved overall understanding of HUS pathogenesis.
    Virulence 08/2013; 4(6). · 3.32 Impact Factor
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    ABSTRACT: Adult bone marrow-derived cells can improve organ function in chronic disease models, ostensibly by the release of paracrine factors. It has, however, been difficult to reconcile this prevailing paradigm with the lack of cell retention within injured organs and their rapid migration to the reticulo-endothelial system. Here we provide evidence that the salutary anti-fibrotic effects of bone marrow-derived early outgrowth cells (EOCs) are more consistent with an endocrine mode of action, demonstrating not only the presence of anti-fibrotic factors in the plasma of EOC-treated rats, but also that EOC conditioned medium (EOC-CM) potently attenuates both TGF-β and angiotensin II-induced fibroblast collagen production in vitro. To examine the therapeutic relevance of these findings in vivo, 5/6 subtotally nephrectomized (SNX) rats, a model of chronic kidney and heart failure characterized by progressive fibrosis of both organs, were randomized to receive intravenous injections of EOC-CM, unconditioned medium or 10(6) EOCs. Rats that received unconditioned medium developed severe kidney injury with cardiac diastolic dysfunction. In comparison, EOC-CM-treated rats demonstrated substantially improved renal and cardiac function and structure, mimicking the changes found in EOC-treated animals. Mass spectrometric analysis of EOC-CM identified proteins that regulate cellular functions implicated in fibrosis. These results indicate that EOCs secrete soluble factor(s) with highly potent anti-fibrotic activity, that when injected intravenously replicate the salutary effects of the cells themselves. Together, these findings suggest that an endocrine mode of action may underlie the effectiveness of cell therapy in certain settings and portend the possibility for systemic delivery of cell-free therapy. Stem Cells 2013.
    Stem Cells 08/2013; · 7.70 Impact Factor
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    ABSTRACT: Escherichia coli O157:H7-associated hemolytic-uremic syndrome (HUS) is characterized by profound prothrombotic abnormalities. Endothelial dysfunction, manifested as dysregulation of angiopoietins-1 and -2 (Ang-1/2), could underlie HUS pathophysiology. We measured Ang-1/2 in 77 children with E. coli O157:H7 infection. Ang-1, Ang-2, and Ang-2:Ang-1 were significantly different in HUS versus the pre-HUS phase of illness or uncomplicated infection. Angiopoietin dysregulation preceded HUS and worsened as HUS developed. In vitro exposure of human microvascular endothelial cells to Shiga toxin recapitulated the in vivo observations. Angiopoietin regulation is profoundly affected before and during HUS, reflecting that subclinical endothelial dysfunction precedes overt microangiopathy.
    The Journal of Infectious Diseases 06/2013; · 5.85 Impact Factor
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    ABSTRACT: The human endothelial nitric oxide synthase (eNOS) mRNA is highly stable in endothelial cells (ECs). Post-transcriptional regulation of eNOS mRNA stability is an important component of eNOS regulation, especially in hypoxic conditions. Here we show that the human eNOS 3' -untranslated region (3' -UTR) contains multiple, evolutionarily conserved pyrimidine (C and CU)-rich sequence elements that are both necessary and sufficient for mRNA stabilization. Importantly, RNA immunoprecipitations and RNA-EMSAs revealed the formation of hnRNP E1-containing ribonucleoprotein (RNP) complexes at these 3' -UTR elements. Knockdown of hnRNP E1 decreased eNOS mRNA half-life, mRNA levels, and protein expression. Significantly, these stabilizing RNP complexes protect eNOS mRNA from the inhibitory effects of its antisense transcript sONE, 3' -UTR-targeting siRNAs, as well as microRNAs, specifically hsa-miR-765, which targets eNOS mRNA stability determinants. Hypoxia disrupts hnRNP E1/eNOS 3' -UTR interactions via increased Akt-mediated serine phosphorylation (including serine 43) and increased nuclear localization of hnRNP E1. These mechanisms account for the decrease in eNOS mRNA stability under hypoxic conditions. Thus, the stabilization of human eNOS mRNA by hnRNP E1-containing RNP complexes serves as a key protective mechanism against the post-transcriptional inhibitory effects of antisense RNA and microRNAs under basal conditions, but is disrupted under hypoxic conditions.
    Molecular and Cellular Biology 03/2013; · 5.04 Impact Factor
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    ABSTRACT: Proximal promoter DNA methylation has been shown to be important for regulating gene expression. However, its relative contribution to the cell-specific expression of EC-enriched genes has not been defined. We used methyl-DNA immunoprecipitation (MeDIP) and bisulfite conversion to analyze the DNA methylation profile of EC-enriched genes in ECs versus non-expressing cell types, both in vitro and in vivo. We show that prototypic EC-enriched genes exhibit functional, differential patterns of DNA methylation in proximal promoter regions of most (eg. CD31, vWF, VE-cadherin and ICAM-2), but not all (eg. VEGFR-1 and VEGFR-2) EC-enriched genes. Comparable findings were evident in cultured ECs, human blood origin ECs and murine aortic ECs. Promoter-reporter episomal transfection assays for eNOS, VE-cadherin and vWF indicated functional promoter activity in cell types where the native gene was not active. Inhibition of DNA methyltransferase activity indicated important functional relevance. Importantly, profiling DNA replication timing patterns indicated that EC-enriched gene promoters with differentially methylated regions replicate early in S-phase in both expressing and non-expressing cell types. Chromatin-based mechanisms are critical for the transcriptional regulation of EC-enriched genes both in vitro and in vivo. Collectively, these studies highlight the functional importance of promoter DNA methylation in controlling vascular endothelial cell gene expression.
    Blood 02/2013; · 9.78 Impact Factor
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    ABSTRACT: A commonly-assumed paradigm holds that the primary genetic determinant of cardiovascular disease resides within the DNA sequence of our genes. This paradigm can be challenged. For example, how do sequence changes in the non-coding region of the genome influence phenotype? Why are all diseases not shared between identical twins? Part of the answer lies in the fact that the environment or exogenous stimuli clearly influence disease susceptibility, but it was unclear in the past how these effects were signalled to the static DNA code. Epigenetics is providing a newer perspective on these issues. Epigenetics refers to chromatin-based mechanisms important in the regulation of gene expression that do not involve changes to the DNA sequence per se. The field can be broadly categorized into three areas: DNA base modifications (including cytosine methylation and cytosine hydroxymethylation), post-translational modifications of histone proteins, and RNA-based mechanisms that operate in the nucleus. Cardiovascular disease pathways are now being approached from the epigenetic perspective, including those associated with atherosclerosis, angiogenesis, ischemia-reperfusion damage, and the cardiovascular response to hypoxia and shear stress, among many others. With increasing interest and expanding partnerships in the field, we can expect new insights to emerge from epigenetic perspectives of cardiovascular health. This paper reviews the principles governing epigenetic regulation, discusses their presently-understood importance in cardiovascular disease, and considers the growing significance we are likely to attribute to epigenetic contributions in the future, as they provide new mechanistic insights and a host of novel clinical applications.
    The Canadian journal of cardiology 01/2013; 29(1):46-57. · 3.12 Impact Factor
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    ABSTRACT: MicroRNA are essential posttranscriptional modulators of gene expression implicated in various chronic diseases. Because microRNA-145 is highly expressed in vascular smooth muscle cells (VSMC) and regulates VSMC fate and plasticity, we hypothesized that it may be a novel regulator of atherosclerosis and plaque stability. Apolipoprotein E knockout mice (ApoE(-/-)) mice were treated with either a microRNA-145 lentivirus under the control of the smooth muscle cell (SMC)-specific promoter SM22α or a SM22α control lentivirus before commencing the Western diet for 12 weeks. The SMC-targeted microRNA-145 treatment markedly reduced plaque size in aortic sinuses, ascending aortas, and brachiocephalic arteries. It also significantly increased fibrous cap area, reduced necrotic core area, and increased plaque collagen content. Cellular plaque composition analyses revealed significantly less macrophages in ApoE(-/-) mice treated with the SMC-specific microRNA-145. These mice also demonstrated marked increases in calponin levels and α-smooth muscle actin-positive SMC areas in their atherosclerotic lesions. Furthermore, lentiviral delivery of microRNA-145 resulted in reduced KLF4 and elevated myocardin expression in aortas from ApoE(-/-) mice, consistent with an effect of microRNA-145 to promote a contractile phenotype in VSMC. VSMC-specific overexpression of microRNA-145 is a novel in vivo therapeutic target to limit atherosclerotic plaque morphology and cellular composition, shifting the balance toward plaque stability vs plaque rupture.
    Circulation 09/2012; 126(11 Suppl 1):S81-90. · 14.95 Impact Factor
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    ABSTRACT: Diarrhea-associated hemolytic uremic syndrome (HUS) caused by Shiga toxin-producing Escherichia coli (STEC) continues to be an important public health threat worldwide. Specific therapies are lacking and patient care remains largely supportive. This review discusses the lessons learned from recent events and summarizes key advances made toward understanding the basic mechanisms involved in the pathogenesis of typical HUS. The recent German outbreak of a hybrid organism resulted in an unprecedented number of HUS cases and drastically changed the face of typical (diarrhea-associated) HUS. New findings on the roles of complement and the CXCR4/SDF-1 pathway in HUS pathogenesis are summarized and novel therapeutic strategies are highlighted. A better understanding of STEC-mediated HUS underlies improved therapeutic approaches. New studies of the mechanistic basis of the disease, together with patient-based studies, have led to key findings with important clinical implications.
    Current opinion in nephrology and hypertension 07/2012; 21(4):433-40. · 3.96 Impact Factor
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    ABSTRACT: The processes by which cells sense and respond to ambient oxygen concentration are fundamental to cell survival and function, and they commonly target gene regulatory events. To date, however, little is known about the link between the microRNA pathway and hypoxia signaling. Here, we show in vitro and in vivo that chronic hypoxia impairs Dicer (DICER1) expression and activity, resulting in global consequences on microRNA biogenesis. We show that von Hippel-Lindau-dependent down-regulation of Dicer is key to the expression and function of hypoxia-inducible factor α (HIF-α) subunits. Specifically, we show that EPAS1/HIF-2α is regulated by the Dicer-dependent microRNA miR-185, which is down-regulated by hypoxia. Full expression of hypoxia-responsive/HIF target genes in chronic hypoxia (e.g. VEGFA, FLT1/VEGFR1, KDR/VEGFR2, BNIP3L, and SLC2A1/GLUT1), the function of which is to regulate various adaptive responses to compromised oxygen availability, is also dependent on hypoxia-mediated down-regulation of Dicer function and changes in post-transcriptional gene regulation. Therefore, functional deficiency of Dicer in chronic hypoxia is relevant to both HIF-α isoforms and hypoxia-responsive/HIF target genes, especially in the vascular endothelium. These findings have relevance to emerging therapies given that we show that the efficacy of RNA interference under chronic hypoxia, but not normal oxygen availability, is Dicer-dependent. Collectively, these findings show that the down-regulation of Dicer under chronic hypoxia is an adaptive mechanism that serves to maintain the cellular hypoxic response through HIF-α- and microRNA-dependent mechanisms, thereby providing an essential mechanistic insight into the oxygen-dependent microRNA regulatory pathway.
    Journal of Biological Chemistry 06/2012; 287(34):29003-20. · 4.60 Impact Factor
  • J J David Ho, H S Jeffrey Man, Philip A Marsden
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    ABSTRACT: Endothelial-derived nitric oxide (NO) is classically viewed as a regulator of vasomotor tone. NO plays an important role in regulating O(2) delivery through paracrine control of vasomotor tone locally and cardiovascular and respiratory responses centrally. Very soon after the cloning and functional characterization of the endothelial nitric oxide synthase (eNOS), studies on the interaction between O(2) and NO made the paradoxical finding that hypoxia led to decreases in eNOS expression and function. Why would decreases in O(2) content in tissues elicit a loss of a potent endothelial-derived vasodilator? We now know that restricting our view of NO as a regulator of vasomotor tone or blood pressure limited deeper levels of mechanistic insight. Exciting new studies indicate that functional interactions between NO and O(2) exhibit profound complexity and are relevant to diseases states, especially those associated with hypoxia in tissues. NOS isoforms catalytically require O(2). Hypoxia regulates steady-state expression of the mRNA and protein abundance of the NOS enzymes. Animals genetically deficient in NOS isoforms have perturbations in their ability to adapt to changes in O(2) supply or demand. Most interestingly, the intracellular pathways for O(2) sensing that evolved to ensure an appropriate balance of O(2) delivery and utilization intersect with NO signaling networks. Recent studies demonstrate that hypoxia-inducible factor (HIF) stabilization and transcriptional activity is achieved through two parallel pathways: (1) a decrease in O(2)-dependent prolyl hydroxylation of HIF and (2) S-nitrosylation of HIF pathway components. Recent findings support a role for S-nitrosothiols as hypoxia-mimetics in certain biological and/or disease settings, such as living at high altitude, exposure to small molecules that can bind NO, or anemia.
    Journal of Molecular Medicine 03/2012; 90(3):217-31. · 4.77 Impact Factor
  • Philip A Marsden
    Seminars in Nephrology 03/2012; 32(2):143-4. · 2.94 Impact Factor
  • Alisha Jamal, H S Jeffrey Man, Philip A Marsden
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    ABSTRACT: We now appreciate that the vascular endothelium plays a crucial role in regulating normal blood vessel physiology in the kidney. The gene products responsible are commonly expressed exclusively, or preferentially, in this cell type. However, despite the importance of regulated gene expression in the vascular endothelium, relatively little is known about the mechanisms that restrict endothelial-specific gene expression to this cell type. Even less is known about how gene expression might be restricted to endothelial cells of discrete regions of the kidney, such as the glomerulus or vasa recta. Although significant progress has been made toward understanding the regulation of endothelial genes through cis/trans paradigms, it has become apparent that additional mechanisms also must be operative. Classic models of transcription in vascular endothelial cells, specifically the cis/trans paradigm, have limitations. For instance, how does the environment have chronic effects on gene expression in endothelial cells after weeks or years? When an endothelial cell divides, how is this information transmitted to daughter cells? Chromatin-based mechanisms, including cell-specific DNA methylation patterns and post-translational histone modifications, recently were shown to play important roles in gene expression. This review investigates the involvement of epigenetic regulatory mechanisms in vascular endothelial cell-specific gene expression using endothelial nitric oxide synthase as a prototypical model.
    Seminars in Nephrology 03/2012; 32(2):176-84. · 2.94 Impact Factor

Publication Stats

6k Citations
1,041.58 Total Impact Points

Institutions

  • 1992–2014
    • University of Toronto
      • • Department of Medicine
      • • Department of Laboratory Medicine and Pathobiology
      • • Saint Michael's Hospital
      Toronto, Ontario, Canada
    • Johns Hopkins University
      • Division of Nephrology
      Baltimore, MD, United States
  • 1994–2013
    • St. Michael's Hospital
      Toronto, Ontario, Canada
  • 2011
    • University of Melbourne
      • Department of Medicine
      Melbourne, Victoria, Australia
  • 2002–2007
    • SickKids
      • Division of Hematology/Oncology
      Toronto, Ontario, Canada
  • 2004
    • Toronto Western Hospital
      Toronto, Ontario, Canada
    • McMaster University
      • Department of Medicine
      Hamilton, Ontario, Canada
  • 2003
    • University Health Network
      Toronto, Ontario, Canada
  • 2002–2003
    • UHN: Toronto General Hospital
      Toronto, Ontario, Canada
  • 1999–2001
    • The Kings College
      Saint Michael, Minnesota, United States
  • 1998
    • Dalhousie University
      Halifax, Nova Scotia, Canada
  • 1997
    • Emory University
      • Department of Internal Medicine
      Atlanta, GA, United States
  • 1991
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
  • 1989
    • Harvard Medical School
      Boston, Massachusetts, United States