Publications by authors named "Emanuela Colombo"

33 Publications

Lessons from S1P receptor targeting in multiple sclerosis.

Pharmacol Ther 2021 Aug 25:107971. Epub 2021 Aug 25.

Institute of Experimental Neurology (INSpe), Division of Neuroscience, IRCCS San Raffaele Hospital, 20132 Milan, Italy. Electronic address:

Sphingosine 1-phosphate (S1P) is a potent bioactive sphingolipid binding to specific G protein-coupled receptors expressed in several organs. The relevance of S1P-S1P receptor axis in the pathophysiology of immune and nervous systems has encouraged the development of S1P receptor modulators for the treatment of neurological, autoimmune and/or inflammatory disorders. Currently, four S1P receptor modulators are approved drugs for multiple sclerosis (MS), an inflammatory disorder of the central nervous system. As main pharmacologic effect, these treatments induce lymphopenia due to the loss of responsiveness to S1P gradients guiding lymphocyte egress from lymphoid organs into the bloodstream. Recent data point to immunological effects of the S1P modulators beyond the inhibition of lymphocyte trafficking. Further, these drugs may cross the blood-brain barrier and directly target CNS resident cells expressing S1P receptors. Here we review the role of S1P signalling in neuroimmunology at the light of the evidences generated from the study of the mechanism of action of S1P receptor modulators in MS and integrate this information with findings derived from neuroinflammatory animal models and in vitro observations. These insights can direct the application of therapeutic approaches targeting S1P receptors in other disease areas.
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http://dx.doi.org/10.1016/j.pharmthera.2021.107971DOI Listing
August 2021

Dysregulated copper transport in multiple sclerosis may cause demyelination via astrocytes.

Proc Natl Acad Sci U S A 2021 Jul;118(27)

Division of Neuroscience, Institute of Experimental Neurology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, 20132, Milan, Italy;

Demyelination is a key pathogenic feature of multiple sclerosis (MS). Here, we evaluated the astrocyte contribution to myelin loss and focused on the neurotrophin receptor TrkB, whose up-regulation on the astrocyte finely demarcated chronic demyelinated areas in MS and was paralleled by neurotrophin loss. Mice lacking astrocyte TrkB were resistant to demyelination induced by autoimmune or toxic insults, demonstrating that TrkB signaling in astrocytes fostered oligodendrocyte damage. In vitro and ex vivo approaches highlighted that astrocyte TrkB supported scar formation and glia proliferation even in the absence of neurotrophin binding, indicating TrkB transactivation in response to inflammatory or toxic mediators. Notably, our neuropathological studies demonstrated copper dysregulation in MS and model lesions and TrkB-dependent expression of copper transporter (CTR1) on glia cells during neuroinflammation. In vitro experiments evidenced that TrkB was critical for the generation of glial intracellular calcium flux and CTR1 up-regulation induced by stimuli distinct from neurotrophins. These events led to copper uptake and release by the astrocyte, and in turn resulted in oligodendrocyte loss. Collectively, these data demonstrate a pathogenic demyelination mechanism via the astrocyte release of copper and open up the possibility of restoring copper homeostasis in the white matter as a therapeutic target in MS.
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http://dx.doi.org/10.1073/pnas.2025804118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271600PMC
July 2021

Laquinimod Modulates Human Astrocyte Function and Dampens Astrocyte-Induced Neurotoxicity during Inflammation.

Molecules 2020 Nov 18;25(22). Epub 2020 Nov 18.

Institute of Experimental Neurology (INSpe), Division of Neuroscience, IRCCS San Raffaele Hospital, 20132 Milan, Italy.

Astrocytes greatly participate to inflammatory and neurotoxic reactions occurring in neurodegenerative diseases and are valuable pharmacological targets to support neuroprotection. Here we used human astrocytes generated from reprogrammed fibroblasts as a cellular model to study the effect of the compound Laquinimod and its active metabolite de-Laquinimod on astrocyte functions and the astrocyte-neuron interaction. We show that human iAstrocytes expressed the receptor for the inflammatory mediator IL1 and responded to it via nuclear translocation of NFκB, an event that did not occur if cells were treated with Laquinimod, indicating a direct anti-inflammatory activity of the drug on the human astrocyte. Similarly, while exposure to IL1 downregulated glial glutamate transporters GLAST and GLT1, treatment with Laquinimod supported maintenance of physiological levels of these proteins despite the inflammatory milieu. Laquinimod also induced nuclear translocation of the aryl hydrocarbon receptor (AHR), suggesting that drug action was mediated by activation of the AHR pathway. However, the drug was effective despite AHR inhibition via CH223191, indicating that AHR signaling in the astrocyte is dispensable for drug responses. Finally, in vitro experiments with rat spinal neurons showed that laquinimod did not exert neuroprotection directly on the neuron but dampened astrocyte-induced neurodegeneration. Our findings indicate that fibroblast-derived human astrocytes represent a suitable model to study astrocyte-neuron crosstalk and demonstrate indirect, partial neuroprotective efficacy for laquinimod.
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http://dx.doi.org/10.3390/molecules25225403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699283PMC
November 2020

Siponimod (BAF312) Activates Nrf2 While Hampering NFκB in Human Astrocytes, and Protects From Astrocyte-Induced Neurodegeneration.

Front Immunol 2020 8;11:635. Epub 2020 Apr 8.

Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system (CNS) with heterogeneous pathophysiology. In its progressive course oligodendrocyte and neuroaxonal damage is sustained by compartmentalized inflammation due to glial dysregulation. Siponimod (BAF312), a modulator of two sphingosine-1-phosphate (S1P) receptors (S1P1 and S1P5) is the first oral treatment specifically approved for active secondary progressive MS. To address potential direct effects of BAF312 on glial function and glia-neuron interaction, we set up a series of functional assays with astrocytes generated from human fibroblasts. These cells displayed the typical morphology and markers of astroglia, and were susceptible to the action of inflammatory mediators and BAF312, because expressing receptors for IL1, IL17, and S1P (namely S1P1 and S1P3). Targeting of S1P signaling by BAF312 inhibited NFκB translocation evoked by inflammatory cytokines, indicating a direct anti-inflammatory activity of the drug on the human astrocyte. Further, while glia cells exposed to IL1 or IL17 downregulated protein expression of glutamate transporters, BAF312-treated astrocytes maintained high levels of GLAST and GLT1 regardless of the presence of inflammatory mediators. Interestingly, despite potential glial susceptibility to S1P signaling via S1P3, which is not targeted by BAF312, NFκB translocation and downregulation of glutamate transporters in response to S1P were inhibited at similar levels by BAF312 and FTY720, another S1P signaling modulator targeting also S1P3. Accordingly, specific inhibition of S1P1 via NIBR-0213 blocked S1P-evoked NFκB translocation, demonstrating that modulation of S1P1 is sufficient to dampen signaling via other S1P receptors. Considering that NFκB-dependent responses are regulated by Nrf2, we measured activation of this critical transcription factor for anti-oxidant reactions, and observed that BAF312 rapidly induced nuclear translocation of Nrf2, but this effect was attenuated in the presence of an inflammatory milieu. Finally, experiments with spinal neurons exposed to astrocyte-conditioned media showed that modulation of S1P or cytokine signaling in astrocytes via BAF312 prevented neurons from astrocyte-induced degeneration. Overall, these experiments on human astrocytes suggest that during neuroinflammation targeting of S1P1 via BAF312 may modulate key astrocyte functions and thereby attain neuroprotection indirectly.
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http://dx.doi.org/10.3389/fimmu.2020.00635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156595PMC
March 2021

Neural Stem Cell Transplantation Induces Stroke Recovery by Upregulating Glutamate Transporter GLT-1 in Astrocytes.

J Neurosci 2016 10;36(41):10529-10544

Neuroimmunology Unit, Institute of Experimental Neurology and

Ischemic stroke is the leading cause of disability, but effective therapies are currently widely lacking. Recovery from stroke is very much dependent on the possibility to develop treatments able to both halt the neurodegenerative process as well as to foster adaptive tissue plasticity. Here we show that ischemic mice treated with neural precursor cell (NPC) transplantation had on neurophysiological analysis, early after treatment, reduced presynaptic release of glutamate within the ipsilesional corticospinal tract (CST), and an enhanced NMDA-mediated excitatory transmission in the contralesional CST. Concurrently, NPC-treated mice displayed a reduced CST degeneration, increased axonal rewiring, and augmented dendritic arborization, resulting in long-term functional amelioration persisting up to 60 d after ischemia. The enhanced functional and structural plasticity relied on the capacity of transplanted NPCs to localize in the peri-ischemic and ischemic area, to promote the upregulation of the glial glutamate transporter 1 (GLT-1) on astrocytes and to reduce peri-ischemic extracellular glutamate. The upregulation of GLT-1 induced by transplanted NPCs was found to rely on the secretion of VEGF by NPCs. Blocking VEGF during the first week after stroke reduced GLT-1 upregulation as well as long-term behavioral recovery in NPC-treated mice. Our results show that NPC transplantation, by modulating the excitatory-inhibitory balance and stroke microenvironment, is a promising therapy to ameliorate disability, to promote tissue recovery and plasticity processes after stroke.

Significance Statement: Tissue damage and loss of function occurring after stroke can be constrained by fostering plasticity processes of the brain. Over the past years, stem cell transplantation for repair of the CNS has received increasing interest, although underlying mechanism remain elusive. We here show that neural stem/precursor cell transplantation after ischemic stroke is able to foster axonal rewiring and dendritic plasticity and to induce long-term functional recovery. The observed therapeutic effect of neural precursor cells seems to underlie their capacity to upregulate the glial glutamate transporter on astrocytes through the vascular endothelial growth factor inducing favorable changes in the electrical and molecular stroke microenvironment. Cell-based approaches able to influence plasticity seem particularly suited to favor poststroke recovery.
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http://dx.doi.org/10.1523/JNEUROSCI.1643-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059427PMC
October 2016

Astrocytes: Key Regulators of Neuroinflammation.

Trends Immunol 2016 09 19;37(9):608-620. Epub 2016 Jul 19.

Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy. Electronic address:

Astrocytes are crucial regulators of innate and adaptive immune responses in the injured central nervous system. Depending on timing and context, astrocyte activity may exacerbate inflammatory reactions and tissue damage, or promote immunosuppression and tissue repair. Recent literature has unveiled key factors and intracellular signaling pathways that govern astrocyte behavior during neuroinflammation. Here we have re-visited in vivo studies on astrocyte signaling in neuroinflammatory models focusing on evidences obtained from the analysis of transgenic mice where distinct genes involved in ligand binding, transcriptional regulation and cell communication have been manipulated in astrocytes. The integration of in vivo observations with in vitro data clarifies precise signaling steps, highlights the crosstalk among pathways and identifies shared effector mechanisms in neuroinflammation.
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http://dx.doi.org/10.1016/j.it.2016.06.006DOI Listing
September 2016

Myeloid cells as target of fingolimod action in multiple sclerosis.

Neurol Neuroimmunol Neuroinflamm 2015 Dec 4;2(6):e157. Epub 2015 Nov 4.

Institute of Experimental Neurology (INSpe), Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Objective: To track the effects of fingolimod, an approved drug for multiple sclerosis (MS), on the activation of myeloid cells from the periphery to the CNS.

Methods: In vitro and ex vivo immunologic studies coupled with flow cytometry were performed to evaluate the action of fingolimod on lipopolysaccharide (LPS)-induced expression of activation markers in human monocytes from healthy participants, participants with untreated MS, and participants with fingolimod-treated MS. In vivo administration of fingolimod during experimental autoimmune encephalomyelitis (EAE) was established to verify the activation state of splenic, CNS infiltrating, and CNS resident myeloid cells ex vivo at flow cytometer.

Results: We found that in vitro exposure of human monocytes to fingolimod inhibited LPS-induced CD25 and CD150 expression and tumor necrosis factor-α (TNF-α) secretion without altering immune cell survival. Further, EAE treatment with fingolimod led to reduced amounts of TNF-α produced by myeloid cells in vivo in the spleen and CNS. Finally, while displaying normal induction of CD25 and CD150 levels at high LPS concentration, monocytes from patients with fingolimod-treated MS showed significantly higher activation threshold at suboptimal LPS stimulation than controls.

Conclusions: The inhibition of myeloid cell activation may be part of the immunosuppressive action of fingolimod and take place in the periphery and in the CNS.
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http://dx.doi.org/10.1212/NXI.0000000000000157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635549PMC
December 2015

Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide.

Ann Neurol 2014 Sep 15;76(3):325-37. Epub 2014 Jul 15.

Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.

Objective: Although astrocytes participate in glial scar formation and tissue repair, dysregulation of the NFκB pathway and of nitric oxide (NO) production in these glia cells contributes to neuroinflammation and neurodegeneration. Here we investigated the role of the crosstalk between sphingosine-1-phosphate (S1P) and cytokine signaling cascades in astrocyte activation and inflammation-mediated neurodegeneration, and addressed the effects of fingolimod on astrocyte-neuron interaction and NO synthesis in vivo.

Methods: Immunohistochemistry, immunofluorescence, and confocal microscopy were used to detect S1P receptors, interleukin (IL) 1R, IL17RA, and nitrosative stress in multiple sclerosis (MS) plaques, experimental autoimmune encephalomyelitis (EAE) spinal cord, and the spinal cord of fingolimod-treated EAE mice. An in vitro model was established to study the effects of S1P, IL1, and IL17 stimulation on NFkB translocation and NO production in astrocytes, on spinal neuron survival, and on astrocyte-neuron interaction. Furthermore, fingolimod efficacy in blocking astrocyte-mediated neurodegeneration was evaluated.

Results: We found coordinated upregulation of IL1R, IL17RA, S1P1, and S1P3 together with nitrosative markers in astrocytes within MS and EAE lesions. In vitro studies revealed that S1P, IL17, and IL1 induced NFκB translocation and NO production in astrocytes, and astrocyte conditioned media triggered neuronal death. Importantly, fingolimod blocked the 2 activation events evoked in astrocytes by either S1P or inflammatory cytokines, resulting in inhibition of astrocyte-mediated neurodegeneration. Finally, therapeutic administration of fingolimod to EAE mice hampered astrocyte activation and NO production.

Interpretation: A neuroprotective effect of fingolimod in vivo may result from its inhibitory action on key astrocyte activation steps.
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http://dx.doi.org/10.1002/ana.24217DOI Listing
September 2014

An intrabody specific for the nucleophosmin carboxy-terminal mutant and fused to a nuclear localization sequence binds its antigen but fails to relocate it in the nucleus.

Biotechnol Rep (Amst) 2014 Sep 27;3:27-33. Epub 2014 May 27.

Department of Biomedical Sciences and Engineering, University of Nova Gorica, Glavni Trg 9, SI-5261 Vipava, Slovenia.

The cytoplasmic accumulation of NPM1 (NPMc+) is found in acute myeloid leukemia (AML) with NPM1 mutation. NPM1 must shuttle between nucleus and cytoplasm to assure physiological protein synthesis and, therefore, the elimination of NPMc+ is not a suitable therapeutic option. We isolated, characterized, and produced a functional scFv intrabody fused to nuclear localization signal(s) (NLS) that does not recognize NPM1 but binds to the mutant-specific C-terminal NES (nuclear export signal) of NPMc+, responsible for its cytoplasmic accumulation. The scFv-NLS fusion accumulated in the nuclei of wild type cells and strongly bound to its antigen in the cytoplasm of NPMc+ expressing cells. However, it failed to relocate the majority of NPMc+ in the nucleus, even when fused to four NLS. Our results show the technical feasibility of producing recombinant intrabodies with defined sub-cellular targeting and nuclear accumulation but the lack of information concerning the features that confer variable strength to the signal peptides impairs the development of biomolecules able to counteract pathological sub-cellular distribution of shuttling proteins.
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http://dx.doi.org/10.1016/j.btre.2014.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466097PMC
September 2014

Autocrine and immune cell-derived BDNF in human skeletal muscle: implications for myogenesis and tissue regeneration.

J Pathol 2013 Oct 12;231(2):190-8. Epub 2013 Aug 12.

Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.

The neurotrophin system has a role in skeletal muscle biology. Conditional depletion of BDNF in mouse muscle precursor cells alters myogenesis and regeneration in vivo. However, the expression, localization and function of BDNF in human skeletal muscle tissue is not known, so the relevance of the rodent findings for human muscle are unknown. Here we address this by combining ex vivo histological investigations on human biopsies with in vitro analyses of human primary myocytes. We found that BDNF was expressed by precursor and differentiated cells both in vitro and in vivo. Differential analysis of BDNF receptors showed expression of p75NTR and not of TrkB in myocytes, suggesting that the BDNF-p75NTR axis is predominant in human skeletal muscle cells. Several in vitro functional experiments demonstrated that BDNF gene silencing or protein blockade in myoblast cultures hampered myogenesis. Finally, histological investigations of inflammatory myopathy biopsies revealed that infiltrating immune cells localized preferentially near p75NTR-positive regenerating fibres and that they produced BDNF. In conclusion, BDNF is an autocrine factor for skeletal muscle cells and may regulate human myogenesis. Furthermore, the preferential localization of BDNF-producing immune cells near p75NTR-positive regenerating myofibres suggests that immune cell-derived BDNF may sustain tissue repair in inflamed muscle.
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http://dx.doi.org/10.1002/path.4228DOI Listing
October 2013

Exacerbation of experimental autoimmune encephalomyelitis by passive transfer of IgG antibodies from a multiple sclerosis patient responsive to immunoadsorption.

J Neuroimmunol 2013 Sep 13;262(1-2):19-26. Epub 2013 Jun 13.

Neuroimmunology and Neuromuscular Disorders Unit, Foundation IRCCS Neurological Institute C. Besta, Via Celoria 11, 20133 Milan, Italy. Electronic address:

The pathogenic role of antibodies in multiple sclerosis (MS) is still controversial. We transferred to mice with experimental autoimmune encephalomyelitis (EAE), animal model of MS, IgG antibodies purified from a MS patient presenting a dramatic clinical improvement during relapse after selective IgG removal with immunoadsorption. Passive transfer of patient's IgG exacerbated motor paralysis and increased mouse central nervous system (CNS) inflammation and demyelination. Binding of patient's IgG was demonstrated in mouse CNS, with a diffuse staining of white matter oligodendrocytes. These data support a growing body of evidence that antibodies can play an important role in the pathobiology of MS.
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http://dx.doi.org/10.1016/j.jneuroim.2013.05.010DOI Listing
September 2013

Changes in serum lipids and blood glucose in non diabetic patients with metabolic syndrome after mixed meals of different composition.

J Nutr Metab 2012 1;2012:215052. Epub 2012 Feb 1.

Centro per lo Studio e la Prevenzione dell'Aterosclerosi, Department of Internal Medicine, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, University of Milan, via F. Sforza 35, 20122 Milan, Italy.

Aims. To investigate the postprandial changes in serum lipoproteins and blood glucose and to verify whether different nutrient composition of the meal elicits different response in patients with (MetS+) and without (MetS-) metabolic syndrome. Research Design and Methods. 50 MetS+ patients and 50 age- and sex-matched MetS- consumed a regular lunch chosen among those more similar to their usual diet. Blood was drawn in the morning after 12-hour fasting and 2 and 4:30 hours after the meal. Results. Serum triglycerides increased more in MetS+ (35%, 4:30 hours after the meal) than in MetS- (29%), HDL-cholesterol decreased 2 hours after the meal in both groups (-4% and -5%, resp.). Blood sugar similarly increased in both groups (19%, 2 hours after the meal in MetS+ and 17% in MetS-) and plasma insulin increased more and remained high longer in MetS+ (73.5 and 52.3 μU/mL, 2 and 4:30 hours after the meal) than in MetS- (46.7 and 21.6 μU/mL). Difference in nutrient composition of the meal (carbohydrate 57%, fat 28% versus carbohydrate 45%, fat 35%) was not associated with differences in postprandial levels of triglycerides, HDL-cholesterol, glucose, and insulin within each group. Conclusions. As compared with MetS-, MetS+ patients show a greater hypertriglyceridemic and hyperinsulinemic response to a regular lunch whatever the carbohydrate or fat content of the meal.
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http://dx.doi.org/10.1155/2012/215052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306966PMC
August 2012

Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration.

J Exp Med 2012 Mar 5;209(3):521-35. Epub 2012 Mar 5.

Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy.

Neurotrophin growth factors support neuronal survival and function. In this study, we show that the expression of the neurotrophin receptor TrkB is induced on astrocytes in white matter lesions in multiple sclerosis (MS) patients and mice with experimental autoimmune encephalomyelitis (EAE). Surprisingly, mice lacking TrkB specifically in astrocytes were protected from EAE-induced neurodegeneration. In an in vitro assay, astrocytes stimulated with the TrkB agonist brain-derived neurotrophic factor (BDNF) released nitric oxide (NO), and conditioned medium from activated astrocytes had detrimental effects on the morphology and survival of neurons. This neurodegenerative process was amplified by NO produced by neurons. NO synthesis in the central nervous system during EAE depended on astrocyte TrkB. Together, these findings suggest that TrkB expression on astrocytes may represent a new target for neuroprotective therapies in MS.
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http://dx.doi.org/10.1084/jem.20110698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3302220PMC
March 2012

A role for inflammatory mediators in the modulation of the neurotrophin receptor p75NTR on human muscle precursor cells.

J Neuroimmunol 2012 Feb 22;243(1-2):100-2. Epub 2011 Dec 22.

Neuroimmunology and Neuromuscular Disorders Unit, Foundation IRCCS Neurological Institute Carlo Besta, Milan, Italy.

The neurotrophin receptor p75NTR is a marker for human differentiation-prone muscle satellite cells and regulates myogenesis. Here, we wondered whether inflammation could modify p75NTR expression on muscle precursor cells in vitro and in vivo. In vitro experiments on human primary skeletal myoblasts demonstrated that exposure to IFN-γ or IL-1α decreased transcript and protein levels of p75NTR. Furthermore, histological investigations showed a reduction in the pool of p75NTR expressing satellite cells in inflammatory myopathy biopsies. These data suggest a link between muscle inflammation and reduction of p75NTR expression on precursor cells.
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http://dx.doi.org/10.1016/j.jneuroim.2011.12.001DOI Listing
February 2012

The lymphoma-associated NPM-ALK oncogene elicits a p16INK4a/pRb-dependent tumor-suppressive pathway.

Blood 2011 Jun 25;117(24):6617-26. Epub 2011 Apr 25.

Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan, Italy.

Oncogene-induced senescence (OIS) is a barrier for tumor development. Oncogene-dependent DNA damage and activation of the ARF/p53 pathway play a central role in OIS and, accordingly, ARF and p53 are frequently mutated in human cancer. A number of leukemia/lymphoma-initiating oncogenes, however, inhibit ARF/p53 and only infrequently select for ARF or p53 mutations, suggesting the involvement of other tumor-suppressive pathways. We report that NPM-ALK, the initiating oncogene of anaplastic large cell lymphomas (ALCLs), induces DNA damage and irreversibly arrests the cell cycle of primary fibroblasts and hematopoietic progenitors. This effect is associated with inhibition of p53 and is caused by activation of the p16INK4a/pRb tumor-suppressive pathway. Analysis of NPM-ALK lymphomagenesis in transgenic mice showed p16INK4a-dependent accumulation of senescent cells in premalignant lesions and decreased tumor latency in the absence of p16INK4a. Accordingly, human ALCLs showed no expression of either p16INK4a or pRb. Up-regulation of the histone-demethylase Jmjd3 and de-methylation at the p16INK4a promoter contributed to the effect of NPM-ALK on p16INK4a, which was transcriptionally regulated. These data demonstrate that p16INK4a/pRb may function as an alternative pathway of oncogene-induced senescence, and suggest that the reactivation of p16INK4a expression might be a novel strategy to restore the senescence program in some tumors.
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http://dx.doi.org/10.1182/blood-2010-08-301135DOI Listing
June 2011

The multifunctional protein nucleophosmin (NPM1) is a human linker histone H1 chaperone.

Biochemistry 2011 Apr 22;50(14):2780-9. Epub 2011 Mar 22.

Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, India.

Linker histone H1 plays an essential role in chromatin organization. Proper deposition of linker histone H1 as well as its removal is essential for chromatin dynamics and function. Linker histone chaperones perform this important task during chromatin assembly and other DNA-templated phenomena in the cell. Our in vitro data show that the multifunctional histone chaperone NPM1 interacts with linker histone H1 through its first acidic stretch (residues 120-132). Association of NPM1 with linker histone H1 was also observed in cells in culture. NPM1 exhibited remarkable linker histone H1 chaperone activity, as it was able to efficiently deposit histone H1 onto dinucleosomal templates. Overexpression of NPM1 reduced the histone H1 occupancy on the chromatinized template of HIV-1 LTR in TZM-bl cells, which led to enhanced Tat-mediated transactivation. These data identify NPM1 as an important member of the linker histone chaperone family in humans.
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http://dx.doi.org/10.1021/bi101835jDOI Listing
April 2011

Human neurotrophin receptor p75NTR defines differentiation-oriented skeletal muscle precursor cells: implications for muscle regeneration.

J Neuropathol Exp Neurol 2011 Feb;70(2):133-42

Neuroimmunology and Neuromuscular Disorders Unit, Foundation IRCCS Neurological Institute Carlo Besta, Milan, Italy.

Satellite cells are resident stem cells of adult skeletal muscle that have roles in tissue repair. Although several efforts have led to the functional characterization of distinct myogenic populations in animal models, the translation of these findings to humans has been limited. Here, we analyzed the expression and function of the neurotrophin receptor p75NTR in human skeletal muscle precursor cells. We combined histological investigations of muscle biopsies with molecular and cellular analyses of primary muscle precursor cells. p75NTR is expressed by most satellite cells in vivo and is a marker for regenerating fibers in inflamed and dystrophic muscle. p75NTR mRNA and protein are also detectable in primary myoblasts, and these levels increase transiently when cell differentiation is triggered. Transcriptome analyses of p75NTR high versus p75NTR low muscle cells showed that p75NTR is the prototype marker for a precursor cell population that has a broad transcriptional repertoire associated with muscle development and maturation. Several in vitro experiments, including receptor blockade and gene silencing in myoblasts, proved that p75NTR specifically regulates myogenesis and dystrophin expression. Taken together, the results indicate that p75NTR is a novel marker of human differentiation-prone muscle precursor cells that is involved in myogenesis in vivo and in vitro.
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http://dx.doi.org/10.1097/NEN.0b013e3182084391DOI Listing
February 2011

A ribosomal protein L23-nucleophosmin circuit coordinates Mizl function with cell growth.

Nat Cell Biol 2008 Sep;10(9):1051-61

Institute for Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Str.2, 35033 Marburg, Germany.

The Myc-associated zinc-finger protein, Miz1, is a negative regulator of cell proliferation and induces expression of the cell-cycle inhibitors p15(Ink4b) and p21(Cip1). Here we identify the ribosomal protein L23 as a negative regulator of Miz1-dependent transactivation. L23 exerts this function by retaining nucleophosmin, an essential co-activator of Miz1 required for Miz1-induced cell-cycle arrest, in the nucleolus. Mutant forms of nucleophosmin found in acute myeloid leukaemia fail to co-activate Miz1 and re-localize it to the cytosol. As L23 is encoded by a direct target gene of Myc, this regulatory circuit may provide a feedback mechanism that links translation of Myc target genes and cell growth to Miz1-dependent cell-cycle arrest.
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http://dx.doi.org/10.1038/ncb1764DOI Listing
September 2008

Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7 gamma.

J Cell Biol 2008 Jul;182(1):19-26

Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy.

Mutations leading to aberrant cytoplasmic localization of nucleophosmin (NPM) are the most frequent genetic alteration in acute myelogenous leukemia (AML). NPM binds the Arf tumor suppressor and protects it from degradation. The AML-associated NPM mutant (NPMmut) also binds p19Arf but is unable to protect it from degradation, which suggests that inactivation of p19Arf contributes to leukemogenesis in AMLs. We report here that NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7gamma, a component of the E3 ligase complex involved in the ubiquitination and proteasome degradation of c-Myc. NPM was required for nucleolar localization and stabilization of Fbw7gamma. As a consequence, c-Myc was stabilized in cells lacking NPM. Expression of NPMmut also led to c-Myc stabilization because of its ability to interact with Fbw7gamma and delocalize it to the cytoplasm, where it is degraded. Because Fbw7 induces degradation of other growth-promoting proteins, the NPM-Fbw7 interaction emerges as a central tumor suppressor mechanism in human cancer.
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http://dx.doi.org/10.1083/jcb.200711040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2447890PMC
July 2008

NPM/ALK binds and phosphorylates the RNA/DNA-binding protein PSF in anaplastic large-cell lymphoma.

Blood 2007 Oct 30;110(7):2600-9. Epub 2007 May 30.

Department of Clinical Medicine, University of Milano-Bicocca, Monza, Italy.

The oncogenic fusion tyrosine kinase nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) induces cellular transformation in anaplastic large-cell lymphomas (ALCLs) carrying the t(2;5) chromosomal translocation. Protein-protein interactions involving NPM/ALK are important for the activation of downstream signaling pathways. This study was aimed at identifying novel NPM/ALK-binding proteins that might contribute to its oncogenic transformation. Using a proteomic approach, several RNA/DNA-binding proteins were found to coimmunoprecipitate with NPM/ALK, including the multifunctional polypyrimidine tract binding proteinassociated splicing factor (PSF). The interaction between NPM/ALK and PSF was dependent on an active ALK kinase domain and PSF was found to be tyrosine-phosphorylated in NPM/ALK-expressing cell lines and in primary ALK(+) ALCL samples. Furthermore, PSF was shown to be a direct substrate of purified ALK kinase domain in vitro, and PSF Tyr293 was identified as the site of phosphorylation. Y293F PSF was not phosphorylated by NPM/ALK and was not delocalized in NPM/ALK(+) cells. The expression of ALK fusion proteins induced delocalization of PSF from the nucleus to the cytoplasm and forced overexpression of PSF-inhibited proliferation and induced apoptosis in cells expressing NPM/ALK. PSF phosphorylation also increased its binding to RNA and decreased the PSF-mediated suppression of GAGE6 expression. These results identify PSF as a novel NPM/ALK-binding protein and substrate, and suggest that PSF function may be perturbed in NPM/ALK-transformed cells.
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http://dx.doi.org/10.1182/blood-2006-01-028647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1988934PMC
October 2007

Changes in serum triglycerides and high-density lipoprotein concentration and composition after a low-fat mixed meal. Effects of gender and insulin resistance.

Intern Emerg Med 2006 ;1(4):287-95

Department of Internal Medicine, University of Milan, Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena, Milan, Italy.

Objective: Postprandial lipemia is generally studied after a test meal that provides most of the calories as fat and that does not reflect the common food intake. We investigated postprandial changes in serum triglycerides (TG) and in high-density lipoprotein (HDL) concentration and composition after a regular meal poor in fat (30% of calories).

Methods: Fifty-four women and 54 men had breakfast at 8:00 a.m. (12% of daily calories) and lunch at 12:30 p.m. (53% of daily calories).

Results: With respect to fasting values, TG increased more in men (24% at 2:30 p.m. and 30% at 5:00 p.m.) than in women (19% and 23%, respectively). HDL cholesterol decreased by 4% both in men and women at 2:30 p.m., and in both genders levels returned towards baseline levels at 5:00 p.m. Apolipoprotein A-I (apo A-I) significantly decreased in men (-3% at 2:30 p.m.), but did not change in women. The apo A-I/HDL cholesterol ratio significantly increased by 3% in men at 2:30 p.m. and by 5% both in men and women at 5:00 p.m. Postprandial serum TG were higher and HDL cholesterol and apo A-I were lower in subjects of both genders with insulin resistance (high HOMA(IR)) than in those with low HOMA(IR). The greatest increase in serum TG (39%) was observed in men with high HOMA(IR). HDL cholesterol and apo A-I significantly decreased and the apo A-I/HDL-C ratio significantly increased only in this subgroup of subjects.

Conclusions: Ingestion of low doses of fat in a mixed meal is followed by variable increases of serum TG, and the greatest response is found in insulin-resistant men. In this subset of subjects, postprandial hypertriglyceridaemia is associated with alterations in HDL that might be consistent with an increased risk of cardiovascular disease.
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http://dx.doi.org/10.1007/BF02934762DOI Listing
February 2007

Delocalization and destabilization of the Arf tumor suppressor by the leukemia-associated NPM mutant.

Cancer Res 2006 Mar;66(6):3044-50

Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.

One third of acute myeloid leukemias (AMLs) are characterized by the aberrant cytoplasmic localization of nucleophosmin (NPM) due to mutations within its putative nucleolar localization signal. NPM mutations are mutually exclusive with major AML-associated chromosome rearrangements and are frequently associated with a normal karyotype, suggesting that they are critical during leukemogenesis. The underlying molecular mechanisms are, however, unknown. NPM is a nucleocytoplasmic shuttling protein that has been implicated in several cellular processes, including ribosome biogenesis, centrosome duplication, cell cycle progression, and stress response. It has been recently shown that NPM is required for the stabilization and proper nucleolar localization of the tumor suppressor p19(Arf). We report here that the AML-associated NPM mutant localizes mainly in the cytoplasm due to an alteration of its nucleus-cytoplasmic shuttling equilibrium, forms a direct complex with p19(Arf), but is unable to protect it from degradation. Consequently, cells or leukemic blasts expressing the NPM mutant have low levels of cytoplasmic Arf. Furthermore, we show that expression of the NPM mutant reduces the ability of Arf to initiate a p53 response and to induce cell cycle arrest. Inactivation of p19(Arf), a key regulator of the p53-dependent cellular response to oncogene expression, might therefore contribute to leukemogenesis in AMLs with mutated NPM.
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http://dx.doi.org/10.1158/0008-5472.CAN-05-2378DOI Listing
March 2006

Nucleophosmin is required for DNA integrity and p19Arf protein stability.

Mol Cell Biol 2005 Oct;25(20):8874-86

Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.

Nucleophosmin (NPM) is a nucleolar phosphoprotein that binds the tumor suppressors p53 and p19(Arf) and is thought to be indispensable for ribogenesis, cell proliferation, and survival after DNA damage. The NPM gene is the most frequent target of genetic alterations in leukemias and lymphomas, though its role in tumorigenesis is unknown. We report here the first characterization of a mouse NPM knockout strain. Lack of NPM expression results in accumulation of DNA damage, activation of p53, widespread apoptosis, and mid-stage embryonic lethality. Fibroblasts explanted from null embryos fail to grow and rapidly acquire a senescent phenotype. Transfer of the NPM mutation into a p53-null background rescued apoptosis in vivo and fibroblast proliferation in vitro. Cells null for both p53 and NPM grow faster than control cells and are more susceptible to transformation by activated oncogenes, such as mutated Ras or overexpressed Myc. In the absence of NPM, Arf protein is excluded from nucleoli and is markedly less stable. Our data demonstrate that NPM regulates DNA integrity and, through Arf, inhibits cell proliferation and are consistent with a putative tumor-suppressive function of NPM.
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http://dx.doi.org/10.1128/MCB.25.20.8874-8886.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1265791PMC
October 2005

G1 checkpoint failure and increased tumor susceptibility in mice lacking the novel p53 target Ptprv.

EMBO J 2005 Sep 18;24(17):3093-103. Epub 2005 Aug 18.

Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology (VIB), University of Ghent, Ghent, Belgium.

In response to DNA damage, p53 activates a G1 cell cycle checkpoint, in part through induction of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Here we report the identification of a new direct p53 target, Ptprv (or ESP), encoding a transmembrane tyrosine phosphatase. Ptprv transcription is dramatically and preferentially increased in cultured cells undergoing p53-dependent cell cycle arrest, but not in cells undergoing p53-mediated apoptosis. This observation was further confirmed in vivo using a Ptprv null-reporter mouse line. A p53-responsive element is present in the Ptprv promoter and p53 is recruited to this site in vivo. Importantly, while p53-dependent apoptosis is intact in mice lacking Ptprv, Ptprv-null fibroblasts and epithelial cells of the small intestine are defective in G1 checkpoint control. Thus, Ptprv is a new direct p53 target and a key mediator of p53-induced cell cycle arrest. Finally, Ptprv loss enhances the formation of epidermal papillomas after exposure to chemical carcinogens, suggesting that Ptprv acts to suppress tumor formation in vivo.
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http://dx.doi.org/10.1038/sj.emboj.7600769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1201350PMC
September 2005

Activation of alpha-diacylglycerol kinase is critical for the mitogenic properties of anaplastic lymphoma kinase.

Blood 2005 Sep 31;106(6):2175-82. Epub 2005 May 31.

Laboratory of Cellular and Molecular Biology, Institute of Clinical Medicine and Applied Biotechnologies, Polytechnic University of the Marche Region, Via Tronto 10/A, 60020 Ancona, Italy.

Oncogenic rearrangements of the tyrosine kinase receptor anaplastic lymphoma kinase (ALK), most commonly represented by the nucleophosmin/ALK fusion protein (NPM/ALK), are involved in the pathogenesis of anaplastic large-cell lymphomas (ALCLs). In an effort to identify new intracellular transducers operative in ALK-positive malignancies, we have investigated the potential involvement of diacylglycerol kinase (DGK). Here we show that alphaDGK is constitutively activated in the NPM/ALK-positive ALCL-derived cell line Karpas 299 and in NPM/ALK-infected 32D hematopoietic cells. These results were further validated in fibroblastic NIH-3T3 cells expressing a previously described chimeric epidermal growth factor receptor (EGFR)/ALK molecule that allows dissection of ALK enzymatic function under conditions of controlled ligand-induced activation. In this cell system, we also show that ALK-mediated alphaDGK activation is dependent on p60src tyrosine kinase, with which alphaDGK forms a complex. The specific inhibition of alphaDGK, obtained by cell treatment with R59949, significantly reduced cellular growth in all cell lines. This result was further confirmed in Karpas 299 cells following specific down-regulation of alphaDGK by RNA interference. Overall, our data indicate that alphaDGK activation is involved in the control of ALK-mediated mitogenic properties.
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http://dx.doi.org/10.1182/blood-2005-01-0316DOI Listing
September 2005

Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc+ AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance.

Blood 2005 Aug 14;106(3):899-902. Epub 2005 Apr 14.

IFOM-IEO Campus, Via Adamello 16, 20139, Milan, Italy.

Approximately one third of acute myeloid leukemias (AMLs) are characterized by aberrant cytoplasmic localization of nucleophosmin (NPMc+ AML), consequent to mutations in the NPM putative nucleolar localization signal. These events are mutually exclusive with the major AML-associated chromosomal rearrangements, and are frequently associated with normal karyotype, FLT3 mutations, and multilineage involvement. We report the gene expression profiles of 78 de novo AMLs (72 with normal karyotype; 6 without major chromosomal abnormalities) that were characterized for the subcellular localization and mutation status of NPM. Unsupervised clustering clearly separated NPMc+ from NPMc- AMLs, regardless of the presence of FLT3 mutations or non-major chromosomal rearrangements, supporting the concept that NPMc+ AML represents a distinct entity. The molecular signature of NPMc+ AML includes up-regulation of several genes putatively involved in the maintenance of a stem-cell phenotype, suggesting that NPMc+ AML may derive from a multipotent hematopoietic progenitor.
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http://dx.doi.org/10.1182/blood-2005-02-0560DOI Listing
August 2005

Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype.

N Engl J Med 2005 Jan;352(3):254-66

Institute of Hematology, University of Perugia, Perugia, Italy.

Background: Nucleophosmin (NPM), a nucleocytoplasmic shuttling protein with prominent nucleolar localization, regulates the ARF-p53 tumor-suppressor pathway. Translocations involving the NPM gene cause cytoplasmic dislocation of the NPM protein.

Methods: We used immunohistochemical methods to study the subcellular localization of NPM in bone marrow-biopsy specimens from 591 patients with primary acute myelogenous leukemia (AML). We then correlated the presence of cytoplasmic NPM with clinical and biologic features of the disease.

Results: Cytoplasmic NPM was detected in 208 (35.2 percent) of the 591 specimens from patients with primary AML but not in 135 secondary AML specimens or in 980 hematopoietic or extrahematopoietic neoplasms other than AML. It was associated with a wide spectrum of morphologic subtypes of the disease, a normal karyotype, and responsiveness to induction chemotherapy, but not with recurrent genetic abnormalities. There was a high frequency of FLT3 internal tandem duplications and absence of CD34 and CD133 in AML specimens with a normal karyotype and cytoplasmic dislocation of NPM, but not in those in which the protein was restricted to the nucleus. AML specimens with cytoplasmic NPM carried mutations of the NPM gene that were predicted to alter the protein at its C-terminal; this mutant gene caused cytoplasmic localization of NPM in transfected cells.

Conclusions: Cytoplasmic NPM is a characteristic feature of a large subgroup of patients with AML who have a normal karyotype, NPM gene mutations, and responsiveness to induction chemotherapy.
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http://dx.doi.org/10.1056/NEJMoa041974DOI Listing
January 2005

Effects of simvastatin on blood pressure in hypercholesterolemic patients: An open-label study in patients with hypertension or normotension.

Curr Ther Res Clin Exp 2004 May;65(3):239-54

Department of Internal Medicine 1, G. Salvini Hospital, Garbagnate Milanese, Milan, Italy.

Background: Simvastatin has been reported to improve endotheliumdependent vascular relaxation in patients with hypercholesterolemia. The consequent decrease in arterial stiffness might be associated with a decrease in blood pressure (BP).

Objective: The aim of this study was to determine whether simvastatin 20 and 40 mg/d have an effect on systolic and diastolic blood pressure (SBP and DBP, respectively) in patients with hypercholesterolemia, and, if so, whether the effect is dose dependent and/or is related to the changes in the serum lipid profile.

Methods: This 6-month, open-label study was conducted at the Lipid Clinics of the Department of Internal Medicine, University of Milan, Maggiore Hospital IRCCS, and of the Department of Internal Medicine 1, G. Salvini Hospital, Garbagnate Milanese (Milan, Italy). Patients aged 18 to 80 years with primary hypercholesterolemia who were following a low-fat, low-cholesterol diet for >2 months before the study were enrolled. Patients at high risk for cardiovascular disease (CVD), according to the National Cholesterol Education Program Adult Treatment Panel II guidelines, were given simvastatin 20 mg (tablet) QD for 3 months, and those at low risk for CVD continued with diet only for 3 months (controls). Efficacy variables included body weight, SBP, DBP, and serum lipid levels (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high density lipoprotein cholesterol [HDL-C], and triglycerides [TG]). At 3 months, patients in the simvastatin + diet group who reached their therapeutic goal continued to receive simvastatin 20 mg/d for 3 additional months. In simvastatintreated patients who were normotensive at baseline or who became normotensive at 3 months but who did not reach the therapeutic goal, the simvastatin dosage was increased to 40 mg/d. Patients in both groups who remained hypertensive at 3 months were switched to hypotensive therapy. In the diet-only group, patients who were formerly normotensive or who became normotensive at 3 months but who did not reach their therapeutic goal continued with diet only or started lipid-lowering therapy. All other patients in the diet-only group continued to be treated with diet only, for 3 additional months. Efficacy variables were measured again at 6 months. Tolerability of simvastatin was assessed at each visit using patient interview and measurement of serum aminotransferase and creatine phosphokinase levels.

Results: The study population comprised 222 patients (132 women, 90 men; mean [SEM] age, 53.9 [0.95] years [range, 23-76 years]); 115 high-risk patients (57 with untreated stage 1 hypertension) were assigned to the simvastatin + diet group, and 107 low-risk patients (29 with untreated stage 1 hypertension) were assigned to the diet-only group. In the simvastatin group, after 3 months of therapy, mean SBP was decreased by 3.9 (1.49) mm Hg (change, -2.9%), mean DBP decreased by 3.0 (0.87) mm Hg (change, -3.7%), mean TC decreased by 90.6 (3.98) mg/dL (change, -27.0%), mean LDL-C decreased by 88.9 (3.88) mg/dL (change, -35.6%), and mean TG decreased by 26.3 (7.34) mg/dL (change, -15.8%) (all, P < 0.001). Mean HDL-C increased by 3.6 (1.16) mg/dL (change, 6.9%; P < 0.001). The BP-lowering effect was found only in patients with hypertension at baseline (n = 57); in these patients, mean SBP decreased by 7.2 (2.44) mm Hg (change, -4.8%; P < 0.005 vs baseline) and DBP decreased by 4.8 (1.29) mm Hg (change, -5.6%; P < 0.001 vs baseline). Also in the simvastatin group, 26 patients (22.6%) achieved their target SBP/DBP. In patients with normotension at baseline (n = 58), neither SBP nor DBP was changed significantly (changes, -0.8 [1.65] and -1.4 [1.15] mm Hg, respectively [-0.6% and -1.8%, respectively]). The changes in serum lipid levels were similar between hypertensive and normotensive patients in the simvastatin group. Forty-one patients (18 hypertensive and 23 normotensive at baseline) were treated with simvastatin 40 mg/d plus diet between months 3 and 6. At 6 months, no further significant decrease was observed in mean BP. In contrast, the expected dose-dependent response was observed for TC and LDL-C levels. In the diet-only group, no significant changes occurred in BP or serum lipid levels. Changes in BP, TC, LDL-C, TG, and HDL-C were significantly greater in the simvastatin + diet group than in the diet-only group (all, P < 0.001). Body weight did not change significantly in either group.

Conclusions: In this group of patients with hypercholesterolemia, the starting dosage of simvastatin (20 mg/d) was associated with reductions in SBP and DBP within 3 months of treatment in patients with hypertension, and this effect was independent of the lipid-lowering properties of the drug. Although the decrease in BP was modest, it is likely clinically relevant. Further studies on this topic are advisable.
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http://dx.doi.org/10.1016/S0011-393X(04)80057-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964554PMC
May 2004
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