DOCSLIB.ORG

(GSNOR) Enhances Vasculogenesis by Mesenchymal Stem Cells

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(GSNOR) Enhances Vasculogenesis by Mesenchymal Stem Cells S-nitrosoglutathione reductase (GSNOR) enhances vasculogenesis by mesenchymal stem cells Samirah A. Gomesa, Erika B. Rangela, Courtney Premera, Raul A. Dulcea, Yenong Caoa, Victoria Floreaa, Wayne Balkana, Claudia O. Rodriguesa,b, Andrew V. Schallyc,d,e,1, and Joshua M. Harea,f,1 aInterdisciplinary Stem Cell Institute, bDepartment of Molecular and Cellular Pharmacology, cDepartment of Pathology, dDivision of Hematology/Oncology, and fDivision of Cardiology, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136; and eEndocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL 33136 Contributed by Andrew V. Schally, November 27, 2012 (sent for review October 31, 2012) Although nitric oxide (NO) signaling promotes differentiation and differentiation of EPCs and MSCs, we reasoned that NO plays maturation of endothelial progenitor cells, its role in the differen- an equivalent role in this process. tiation of mesenchymal stem cells (MSCs) into endothelial cells Accordingly, we tested the hypothesis that NO signaling, me- remains controversial. We tested the role of NO signaling in MSCs diated by small molecular weight thiols (molecular weight < 500), derived from WT mice and mice homozygous for a deletion of promotes MSC differentiation into endothelial cells. To test our − − S-nitrosoglutathione reductase (GSNOR / ), a denitrosylase that hypothesis, we assessed the functional consequences of deletion − − regulates S-nitrosylation. GSNOR / MSCs exhibited markedly of S-nitrosoglutathione reductase (GSNOR), which in turn diminished capacity for vasculogenesis in an in vitro Matrigel increases S-nitrosothiols (17, 18), on MSC-mediated vasculo- − − tube–forming assay and in vivo relative to WT MSCs. This decrease genesis. We report that paradoxically, MSCs from GSNOR / was associated with down-regulation of the PDGF receptorα mice exhibit diminished endothelial differentiation, thereby − − (PDGFRα) in GSNOR / MSCs, a receptor essential for VEGF-A demonstrating an inhibitory effect of S-nitrosylation on vascu- action in MSCs. Pharmacologic inhibition of NO synthase with logenesis mediated by MSCs. G L-N -nitroarginine methyl ester (L-NAME) and stimulation of growth hormone–releasing hormone receptor (GHRHR) with GHRH agonists Results −/− augmented VEGF-A production and normalized tube formation in Murine Bone Marrow MSC Characterization. Both WT and GSNOR - −/− GSNOR MSCs, whereas NO donors or PDGFR antagonist re- derived MSCs were spindle shaped, adherent to plastic tissue duced tube formation ∼50% by murine and human MSCs. The culture dishes (Fig. S1A), and negative for Lineage, a mixture of antagonist also blocked the rescue of tube formation in hematopoietic markers, CD34 and CD45, and positive for stem −/− GSNOR MSCs by L-NAME or the GHRH agonists JI-38, MR-409, cell antigens SCA-1, CD73, CD90.2, and CD105 (Fig. S1 B and C). and MR-356. Therefore, GSNOR−/− MSCs have a deficient capacity for endothelial differentiation due to downregulation of PDGFRα NO Signaling and MSCs. Denitrosylation is controlled in significant related to NO/GSNOR imbalance. These findings unravel important part by GSNOR, a unique and specific enzyme for which S-nitro- aspects of modulation of MSCs by VEGF-A activation of the PDGFR soglutathione (GSNO) is the substrate (18) (Fig. S2A). Neither −/− and illustrate a paradoxical inhibitory role of S-nitrosylation sig- MSCs (Fig. S2 B and C) nor liver (Fig. S2D)fromGSNOR mice naling in MSC vasculogenesis. Accordingly, disease states charac- expresses GSNOR. NOS1 and NOS2 were constitutively expressed terized by NO deficiency may trigger MSC-mediated vasculogenesis. in both strains of MSCs (Fig. S2 E and F), whereas NOS3 expres- fi These ndings have important implications for therapeutic applica- sion was absent from both strains (Fig. S2G). Interestingly, NOS1 −/− tion of GHRH agonists to ischemic disorders. mRNA was ∼100-fold higher in GSNOR mice (2.7 × 103 ± 3 × 102 absolute number of transcripts, ΔCt) compared with WT MSCs – angiogenesis | nitroso redox imbalance (2 × 104 ± 2 × 103, P < 0.05; Fig. S2E). Despite the up-regulation of NOS1, actual NO production, measured by 4,5-diamino-fluores- itric oxide (NO) and VEGF signaling promotes vasculogenesis cein diacetate (DAF-2DA), was nearly identical between the Nby endothelial progenitor cells (EPCs) (1–5). For example, strains (Fig. S2H). Thus, GSNOR deficiency up-regulates NOS1 −/− mice deficient in endothelial NO synthase (NOS3 ) show re- but does not lead to increased NO production. duced VEGF-induced mobilization of bone marrow progenitor − − cells to sites of injury (4). In EPC-mediated vasculogenesis, VEGF-A GSNOR / MSCs Exhibit Impaired Formation of Capillary Tube–Like activates its major receptor [VEGF receptor 2 (VEGFR2)], trig- Structures in Vitro. Next we used a Matrigel assay to analyze the gering cell differentiation into mature endothelial cells (ECs) and ability of MSCs to form tube-like structures in vitro. Cells were grown in endothelial medium (EGM-2; Lonza) for 1 wk before enhancing angiogenesis (6, 7). −/− Mesenchymal stem cells (MSCs) also participate in postnatal plating on Matrigel. Surprisingly, GSNOR -derived MSCs angiogenesis (8, 9), and vascular pericytes, which are crucial for formed significantly fewer (29.9 ± 11.75 vs. 50.2 ± 14.04, P < maintaining vascular integrity, share similar phenotypic features 0.001) and shorter (62.8 ± 14.0 vs. 124.2 ± 49.0 μm, P < 0.001) with MSCs (10). Exogenously administered, MSCs readily form new capillaries and medium-sized arteries (11, 12), properties important for the tissue regenerative capacity of MSCs (13). We Author contributions: S.A.G., W.B., and J.M.H. designed research; S.A.G., E.B.R., C.P., R.A.D., Y.C., V.F., and C.O.R. performed research; S.A.G. and J.M.H. analyzed data; A.V.S. and J.M.H. and others have shown that MSCs differentiate into endothelial contributed new reagents/analytic tools; and S.A.G., E.B.R., C.O.R., A.V.S., and J.M.H. wrote cells in vitro (14) and in vivo and contribute to neovascularization, the paper. particularly during tissue ischemia and tumor vascularization (8, The authors declare no conflict of interest. 11, 12, 15). As with EPCs, VEGF also plays an important role in Freely available online through the PNAS open access option. stimulating MSC differentiation, but does so by activating the See Commentary on page 2695. PDGF receptor (PDGFR) as opposed to the VEGFR2, which is 1To whom correspondence may be addressed. E-mail: [email protected] or jhare@ absent on MSCs (16). However, the impact of NO signaling in the med.miami.edu. differentiation of MSCs into endothelial cells has not been pre- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. viously tested. Given the similar signaling involved in endothelial 1073/pnas.1220185110/-/DCSupplemental. 2834–2839 | PNAS | February 19, 2013 | vol. 110 | no. 8 www.pnas.org/cgi/doi/10.1073/pnas.1220185110 Downloaded by guest on September 27, 2021 SEE COMMENTARY − − − − Fig. 1. Impaired capillary tube–like formation from GSNOR / MSCs in vitro. (A) Representative images of tube-like formation by WT and GSNOR / MSCs plated on Matrigel-coated plates for 0, 6, and 24 h in the presence of vehicle (rows 1 and 3) or 15 μmol/L L-NAME (rows 2 and 4) (magnification: 10×). Quantification of the number (B) and length (μm) (C) of tubes at 24 h (n ≥ 3, *P < 0.001 vs. WT, †P < 0.001 vs. GSNOR−/−). tubes than those derived from WT mice (Fig. 1 A–C). To test (Fig. 2K). Furthermore, incubation with GSNO down-regu- whether this impairment was NO-mediated, we inhibited NO lated PDGFRα by approximately twofold and up-regulated −/− production in GSNOR MSCs with the NO synthase inhibitor VEGF-A by ∼2.5-fold in WT MSCs, supporting the actions of low- G L-N -nitroarginine methyl ester (L-NAME). This treatment molecular-weight thiols in mediating this phenotype (Fig. S5A). completely normalized the number (49.9 ± 14.8, P < 0.001) and −/− Finally, in GSNOR MSCs, inhibition of NOS with L-NAME CELL BIOLOGY ± μ P < −/− length (82.8 20.5 m, 0.001) of GSNOR tubes (Fig. 1 augmented VEGF-A production ∼4.5-fold (Fig. 3A), demon- A–C ), indicating that inhibition of NO production restores net- strating that NO levels modulate VEGF-A production. Activa- work formation by MSCs. L-NAME had no effect on WT MSC tion of the GHRH receptor, with JI-38, a synthetic agonist, also − − tube formation; however, treatment with the NO donors, increased VEGF-A production by 2.8-fold in GSNOR / MSCs S-nitrosoglutathione (GSNO) and S-nitroso-N-acetyl-D,L-penicil- (Fig. 3B). lamine (SNAP), impaired tube formation (15.6 ± 9.0 and 31.8 ± P < ± ± 9.9, 0.001) and decreased tube length (98.4 56.6 and 57.1 VEGF-A/PDGFR Signaling Is a Key in MSC-Mediated Vasculogenesis. 24.9 μm, P < 0.001) by WT MSCs, confirming that small molecular α S We next examined whether inhibition of PDGFR , using a spe- weight -nitrosothiols inhibit the vasculogenic potential of MSCs cific PDGFR IV antagonist (PIV), could reduce tube formation (Fig. S3 A–C). by MSCs. Treatment with PIV (0.1 μmol/L) impaired tube for- − − ∼ C D A MSCs from NOS2 / Mice Produce Enhanced Capillary Tube–Like mation in both WT ( 2.6-fold; Fig. 3 and ; Fig. S6 ) and −/− ∼ E F B Formation in Vitro. We also tested the impact of reducing in- GSNOR MSCs ( 4.1 fold; Fig. 3 and ; Fig. S6 ). How- −/− tracellular NO production by assessing the vasculogenic potential ever, the impact of PIV was much greater on GSNOR tubes − − of MSCs isolated from mice lacking NOS2 (NOS2 / ). Signifi- than WT. In addition, while treatment with L-NAME rescued − − − − cantly, MSCs from NOS2 / mice formed more tubes (92.8 ± 26.0 tube formation by GSNOR / MSCs, PIV counteracted this ef- −/− vs.
Load more

Recommended publications
  • Reduced Renal Methylarginine Metabolism Protects Against Progressive Kidney Damage
    BASIC RESEARCH www.jasn.org Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage † James A.P. Tomlinson,* Ben Caplin, Olga Boruc,* Claire Bruce-Cobbold,* Pedro Cutillas,* † ‡ Dirk Dormann,* Peter Faull,* Rebecca C. Grossman, Sanjay Khadayate,* Valeria R. Mas, † | Dorothea D. Nitsch,§ Zhen Wang,* Jill T. Norman, Christopher S. Wilcox, † David C. Wheeler, and James Leiper* *Medical Research Council Clinical Sciences Centre, Imperial College, London, United Kingdom; †Centre for Nephrology, UCL Medical School Royal Free, London, United Kingdom; ‡Translational Genomics Transplant Laboratory, Transplant Division, Department of Surgery, University of Virginia, Charlottesville, Virginia; §Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom; and |Hypertension, Kidney and Vascular Research Center, Georgetown University, Washington, DC ABSTRACT Nitric oxide (NO) production is diminished in many patients with cardiovascular and renal disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and elevated plasma levels of ADMA are associated with poor outcomes. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is a methylarginine- metabolizing enzyme that reduces ADMA levels. We reported previously that a DDAH1 gene variant associated with increased renal DDAH1 mRNA transcription and lower plasma ADMA levels, but counterintuitively, a steeper rate of renal function decline. Here, we test the hypothesis that reduced renal-specific
    [Show full text]
  • By Norepinephrine and Inactivated by NO and Cgmp (Medial Basal Hypothalami/Luteinizing Hormone-Releasing Hormone/Camp/Arginine/Nitroarginine Methyl Ester) G
    Proc. Natl. Acad. Sci. USA Vol. 93, pp. 4246-4250, April 1996 Physiology Nitric oxide synthase content of hypothalamic explants: Increased by norepinephrine and inactivated by NO and cGMP (medial basal hypothalami/luteinizing hormone-releasing hormone/cAMP/arginine/nitroarginine methyl ester) G. CANTEROS*, V. RErroRI*, A. GENARO*, A. SUBURO*, M. GIMENO*, AND S. M. MCCANNtt *Centro de Estudios Farmacologicos y Botanicos, Consejo Nacional de Investigaciones Cientificas y Tecnicas, Serrano 665, 1414 Buenos Aires, Argentina; and tPennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808-4124 Contributed by S. M. McCann, December 26, 1995 ABSTRACT Release of luteinizing hormone (LH)- pituitary gland. There it releases LH, which induces ovulation releasing hormone (LHRH), the hypothalamic peptide that and ovarian steroid secretion in females and testosterone controls release of LH from the adenohypophysis, is con- secretion in males (3). Since NO controls LHRH release in the trolled by NO. There is a rich plexus of nitric oxide synthase arcuate nucleus-median eminence region, where axons of (NOS)-containing neurons and fibers in the lateral median LHRH neurons terminate on the portal capillaries (2), we eminence, intermingled with terminals of the LHRH neurons. expected to find NOergic neurons in this region. Indeed, in the To study relations between NOS and LHRH in this brain present study we found a large number of NOergic cell bodies region, we measured NOS activity in incubated medial basal and fibers in the arcuate-median eminence region. hypothalamus (MBH). NOS converts [l4C]arginine to equimo- This study was initiated to determine if we could measure lar quantities of [14C]citrulline plus NO, which rapidly decom- NOS activity in incubated medial basal hypothalami (MBHs) poses.
    [Show full text]
  • S-Nitrosylation Drives Cell Senescence and Aging in Mammals By
    S-nitrosylation drives cell senescence and aging in PNAS PLUS mammals by controlling mitochondrial dynamics and mitophagy Salvatore Rizzaa,1, Simone Cardacib,1, Costanza Montagnaa,c,1, Giuseppina Di Giacomod,2, Daniela De Zioa, Matteo Bordid, Emiliano Maiania, Silvia Campellod,e, Antonella Borrecaf, Annibale A. Pucag,h, Jonathan S. Stamleri,j, Francesco Cecconia,d,k, and Giuseppe Filomenia,d,3 aDanish Cancer Society Research Center, Center for Autophagy, Recycling and Disease, 2100 Copenhagen, Denmark; bDivision of Genetics and Cell Biology, Institute for Research and Health Care San Raffaele (IRCCS) Scientific Institute, 20132 Milan, Italy; cInstitute of Sports Medicine Copenhagen, Bispebjerg Hospital, 2400 Copenhagen, Denmark; dDepartment of Biology, Tor Vergata University, 00133 Rome, Italy; eIRCCS Fondazione Santa Lucia, 00146 Rome, Italy; fInstitute of Cellular Biology and Neuroscience, National Research Council, 00143 Rome, Italy; gCardiovascular Research Unit, IRCCS Multimedica, 20138 Milan, Italy; hDipartimento di Medicina e Chirurgia, University of Salerno, 84084 Fisciano Salerno, Italy; iInstitute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH 44106; jHarrington Discovery Institute, University Hospitals Case Medical Center, Cleveland, OH 44106; and kDepartment of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children’s Hospital, 00146 Rome, Italy Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved March 1, 2018 (received for review January 9, 2018) S-nitrosylation, a prototypic redox-based posttranslational modifi- found in experimental models of aging, supporting the idea that cation, is frequently dysregulated in disease. S-nitrosoglutathione GSNOR preserves cellular function. reductase (GSNOR) regulates protein S-nitrosylation by function- The free radical theory of aging postulates that oxidative ing as a protein denitrosylase.
    [Show full text]
  • Proceeding of the Symposium NITRIC OXIDE Basic Regulations And
    Proceeding of the Symposium NITRIC OXIDE Basic Regulations and Pharmacological Interventions September 21-24, 2005, Tucepi, Croatia Abstracts are presented in the alphabetical order of the first author names and are printed without editing in the submitted form. The Editorial Office of Physiological Research disclaims any responsibility for errors that may have been made in abstracts submitted by the authors. Vol. 55 Physiol. Res. 2006 1P VASODILATORY RESPONS ES UNDER HYPOXIC responses of myocardium to NOD and in adaptive responses of these CONDITION: ROLE OF PGI2 AND NO hearts to ischemic stress. The results point also to the possible I. Juránek, V. Bauer, J. Donnerer1, F. Lembeck1, B.A. Peskar1 relationship between ERK pathway and activation of eNOS and/or Institute of Experimental Pharmacology, Slovak Academy of Sciences, tissue MMP-2. Bratislava, Slovakia; 1Institute of Experimental and Clinical 1. Strohm et. al., J. Cardiovasc. Pharmacol. 2000, 36:218-229 Pharmacology, Medical University, Graz, Austria. Supported by VEGA SR No 2/3123/25, 2/5110/25, APVT 51-013802, SP51/0280900/ 0280901, SP51/028000/0280802. Aim of the present study was to test hypothesis that low availability of oxygen in hypoxic tissue should inhibit oxygenation of arachidonic acid and thereby result in inhibition of eicosanoid synthesis in vivo. Perfusion of the isolated rabbit ear with normoxic or hypoxic medium DUAL ROLE OF NO IN SUSCEPTIBILITY TO ISCHEMIA/ was applied. Eicosanoid biosynthesis and functional responses of the REPERFUSION INJURY IN THE RAT HEART vascular bed were followed. Simultaneous recording of prostaglandin I2 E. Andelová, M. Pintérová, P. Šimoncíková, M. Barancík, M. release and peripheral resistance of t he preparation revealed that lack of Ondrejcáková, *O.
    [Show full text]
  • Viagra, INN-Sildenafil
    SCIENTIFIC DISCUSSION This module reflects the initial scientific discussion for the approval of VIAGRA. This scientific discussion has been updated until 1 December 2002. For information on changes after this date please refer to module 8B. 1. Introduction Male erectile dysfunction (ED) has been defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance as part of the overall process of male sexual function (NIH Consensus Conference, 1993). ED can have a profound impact on the quality of life with subjects often reporting increased anxiety, loss of self-esteem, lack of self-confidence, tension and difficulty in the relationship with their partner. The prevalence of ED has been found to be associated with age. Complete ED has an estimated prevalence of about 5% in men aged 40 years to 15% at age 70 years. It should be recognised that desire, orgasmic capacity and ejaculatory capacity may be intact even in the presence of erectile dysfunction or may be deficient to some extent and contribute to the sense of inadequate sexual function. The term impotence, together with its pejorative implications, is less precise and should not be used. The degree of erectile dysfunction can vary and may range from a partial decrease in penile rigidity to complete erectile failure and the frequency of these failures may also range from “a few times a year” to “usually unable to obtain an erection”. ED is often multifactorial in etiology (organic, psychogenic, or mixed). Sometimes ED is related to stress problems with the sexual partner or transient psychological factors.
    [Show full text]
  • Maternal Tadalafil Therapy for Fetal Growth Restriction Prevents Non
    www.nature.com/scientificreports OPEN Maternal tadalafl therapy for fetal growth restriction prevents non‑alcoholic fatty liver disease and adipocyte hypertrophy in the ofspring Takuya Kawamura, Hiroaki Tanaka, Ryota Tachibana, Kento Yoshikawa, Shintaro Maki, Kuniaki Toriyabe, Hiroki Takeuchi, Shinji Katsuragi, Kayo Tanaka* & Tomoaki Ikeda We aimed to investigate the efects of maternal tadalafl therapy on fetal programming of metabolic function in a mouse model of fetal growth restriction (FGR). Pregnant C57BL6 mice were divided into the control, L‑NG‑nitroarginine methyl ester (L‑NAME), and tadalafl + L‑NAME groups. Six weeks after birth, the male pups in each group were given a high‑fat diet. A glucose tolerance test (GTT) was performed at 15 weeks and the pups were euthanized at 20 weeks. We then assessed the histological changes in the liver and adipose tissue, and the adipocytokine production. We found that the non‑alcoholic fatty liver disease activity score was higher in the L‑NAME group than in the control group (p < 0.05). Although the M1 macrophage numbers were signifcantly higher in the L‑NAME/ high‑fat diet group (p < 0.001), maternal tadalafl administration prevented this change. Moreover, the epididymal adipocyte size was signifcantly larger in the L‑NAME group than in the control group. This was also improved by maternal tadalafl administration (p < 0.05). Further, we found that resistin levels were signifcantly lower in the L‑NAME group compared to the control group (p < 0.05). The combination of exposure to maternal L‑NAME and a high‑fat diet induced glucose impairment and non‑alcoholic fatty liver disease.
    [Show full text]
  • Example of How Amehsi Specification Indicators Can Be Mapped to Health
    Example of how Amehsi Specification Indicators can be Mapped to Health Conditions and Health Statuses The information presented here may be covered by copyrights and patents Some of the Amehsi Factors which can be alleviated using Amehsi Specification Recommendations and Demise Oncology Leukemia Lymphoma HIV Information. This document may be protected by copyrights and patents Choline Deficiency or Circumstantial Choline Deficiency from upregulated Choline Kinase Pathway or Kennedy Pathway Factors Causal Causal Causal Causal Causal Homocysteine Required as Symptom, Correlated and Incipiently Causal, inhibits PEMT Required Causal Causal Causal S-Adenosyl Homocysteine Downregulat Required as Symptom, Correlated and Incipiently Causal, inhibits PEMT Required Causal ed PEMT Causal Trimethylamine-N-Oxide Causal, inhibits PEMT Causal Causal Causal Incipient Enabler Choline Kinase Upregulation Causal Required Required uNOS Required Required as both PEMT1 or PEMT2 since Diagnostic Assay sometimes does not report if one of these is inhibited while the other is not. PEMT produces a Monomethylethanolamine that Phosphatidylethanolamine deteriorates PCBs, Dioxins, Aryl Methyltransferase Downregulation Cyclic Hydrocarbons, Alkyl Halides, other Carcinogens and produces Serine Proteases that catabolize Amino acids to thier most basic structures, resulting in purified cellular environment and embryonic Causal cellular plasticity Required Required Required Inducible Nitric Oxide Synthase, Required, inhibits PEMT and upregulated Choline kinase, as well as
    [Show full text]
  • Effects of Nitric Oxide Synthase Inhibitors on Equine and Bovine Follicular Dynamics and Steroidogenesis
    Louisiana State University LSU Digital Commons LSU Historical Dissertations and Theses Graduate School 2001 Effects of Nitric Oxide Synthase Inhibitors on Equine and Bovine Follicular Dynamics and Steroidogenesis. Carlos Roberto fontes Pinto Louisiana State University and Agricultural & Mechanical College Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_disstheses Recommended Citation Pinto, Carlos Roberto fontes, "Effects of Nitric Oxide Synthase Inhibitors on Equine and Bovine Follicular Dynamics and Steroidogenesis." (2001). LSU Historical Dissertations and Theses. 430. https://digitalcommons.lsu.edu/gradschool_disstheses/430 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Historical Dissertations and Theses by an authorized administrator of LSU Digital Commons. For more information, please contact [email protected]. INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps.
    [Show full text]
  • Effect of Age on Bone Mineral Density and the Serum Concentration of Endogenous Nitric Oxide Synthase Inhibitors in Rats
    Comparative Medicine Vol 52, No 3 Copyright 2002 June 2002 by the American Association for Laboratory Animal Science Pages 224-228 Effect of Age on Bone Mineral Density and the Serum Concentration of Endogenous Nitric Oxide Synthase Inhibitors in Rats Rong Lu, PhD,1 Chang-Ping Hu, PhD,1 Xian-Ping Wu, MD,2 Er-Yuan Liao, MD,2 and Yuan-Jian Li, MD1,* Results of previous studies have indicated that bone mineral density (BMD) is decreased in aged animals and elderly humans, and that treatment with nitric oxide (NO) donors prevents bone loss. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, can inhibit NO synthesis. In the study reported here, we examined age-related changes in the serum content of ADMA and in BMD in various skeletal regions. The BMD in the lumbar part of the spine, the femur, and the tibia in 12-month-old rats was markedly increased, compared with that in 6-month-old rats, and the BMD in 20-month-old rats was decreased, compared with that in 12-month- old rats. Serum concentration of ADMA in 20-month-old rats was significantly increased, compared with that in 6- or 12-month-old rats. A similar age-related change in the concentration of lipid peroxide also was seen in the three age groups. These results suggest that the increased amount of endogenous ADMA may be associated with an age- related decrease in BMD in rats. Osteoporosis has been defined as a disease characterized by normal adult bone, but is largely expressed in response to in- decreased bone mineral density (BMD), leading to enhanced flammatory stimuli (10, 11).
    [Show full text]
  • Lessons Learned
    Prevention and Reversal of Chronic Disease Copyright © 2019 RN Kostoff PREVENTION AND REVERSAL OF CHRONIC DISEASE: LESSONS LEARNED By Ronald N. Kostoff, Ph.D., School of Public Policy, Georgia Institute of Technology 13500 Tallyrand Way, Gainesville, VA, 20155 [email protected] KEYWORDS Chronic disease prevention; chronic disease reversal; chronic kidney disease; Alzheimer’s Disease; peripheral neuropathy; peripheral arterial disease; contributing factors; treatments; biomarkers; literature-based discovery; text mining ABSTRACT For a decade, our research group has been developing protocols to prevent and reverse chronic diseases. The present monograph outlines the lessons we have learned from both conducting the studies and identifying common patterns in the results. The main product of our studies is a five-step treatment protocol to reverse any chronic disease, based on the following systemic medical principle: at the present time, removal of cause is a necessary, but not necessarily sufficient, condition for restorative treatment to be effective. Implementation of the five-step treatment protocol is as follows: FIVE-STEP TREATMENT PROTOCOL TO REVERSE ANY CHRONIC DISEASE Step 1: Obtain a detailed medical and habit/exposure history from the patient. Step 2: Administer written and clinical performance and behavioral tests to assess the severity of symptoms and performance measures. Step 3: Administer laboratory tests (blood, urine, imaging, etc) Step 4: Eliminate ongoing contributing factors to the chronic disease Step 5: Implement treatments for the chronic disease This individually-tailored chronic disease treatment protocol can be implemented with the data available in the biomedical literature now. It is general and applicable to any chronic disease that has an associated substantial research literature (with the possible exceptions of individuals with strong genetic predispositions to the disease in question or who have suffered irreversible damage from the disease).
    [Show full text]
  • Sociedade Brasileira De Cardiologia • ISSN-0066-782X • Volume 108, Nº 5, May 2017
    www.arquivosonline.com.br Sociedade Brasileira de Cardiologia • ISSN-0066-782X • Volume 108, Nº 5, May 2017 Figure 1 – Coronary artery disease (CAD) progression on coronary computed tomography angiography (CCTA) in a 58-year-old male presenting a very mild CAD in the proximal left anterior descending coronary artery at baseline (A). Evident disease progression is seen at 13 months at the same site, with moderate luminal stenosis (B) best appreciated in the vessel’s transverse plane (arrowhead). Page 397 Editorial Effect of Lactation on myocardial vulnerability to ischemic insult in rats Challenges of Translational Science Assessment of Carotid Intima-Media Thickness as an Early Marker Of Special Article Vascular Damage In Hypertensive Children Data Sharing: A New Editorial Initiative of the International Committee Review Article of Medical Journal Editors. Implications for the Editors´ Network Viabilidade Miocárdica pela Ressonância Magnética Cardíaca Original Articles Viewpoint Factors Associated With Coronary Artery Disease Progression Prediction Models for Decision-Making on Chagas Disease Assessed By Serial Coronary Computed Tomography Angiography Anatomopathological Session Relationship between Resting Heart Rate, Blood Pressure and Pulse Case 2/2017 – 56-Year-Old Male with Refractory Heart Failure, Pressure in Adolescents Systemic Arterial Hypertension and Aortic Valve Stenosis That Led to Self-Reported High-Cholesterol Prevalence in the Brazilian Population: Heart Transplantation Analysis of the 2013 National Health Survey Case
    [Show full text]
  • COST844 Meeting the Role of Nitric Oxide in Cardiovascular System
    COST844 Meeting The Role of Nitric Oxide in Cardiovascular System April 8-10, 2005, Bratislava, Slovakia Abstracts are presented in the alphabetical order of the first author names and are printed without editing in the submitted form. The Committees of the Czech and the Slovak Physiological Societies and the Editorial Office of Physiological Research disclaim any responsibility for errors that may have been made in abstracts submitted by the authors. Vol. 54 Physiol. Res. 2005 51P POLYPHENOLS: PROTECTION OF NEUROVASCULAR UNIT THE ROLE OF INTRACELLULAR PROTEIN KINASE IN STROKE AND INHIBITION OF IN—STENT—NEOINTIMAL PATHWAYS IN THE EFFECTS OF CHRONIC NOS GROWTH R Andriantsitohaina1, Y Curin1,2, MF Ritz2, R Gérald3, A INHIBITION IN THE RAT HEART M. Barancik, P. Simoncikova, Alvès4, A Mendelowitsch2, M Elbaz5, 1UMR CNRS 7081, Illkirch, M. Strniskova, 1O. Pechanova, T. Ravingerova. Institute for Heart France, 2Neurosurgery lab, Basel University Hospital, Basel, Research,1 Institute of Normal and Pathological Physiology, Slovak Switzerland, 3 Cardiology Hautepierre, Strasbourg, France, Academy of Sciences, Slovak Republic 4Biomatech, Pathology Institute, Chasse-sur-rhône, France 5Cardiology Rangueil, Toulouse University Hospital, France Nitric oxide (NO) has been implicated in the mechanisms of cardiac adaptation to ischemic stress but the impact of chronic NO deficiency Epidemiological studies have suggested that diet rich in polyphenols (NOD) on the mechanisms of ischemic tolerance has not been can reduce the risk of cardiovascular diseases. Indeed, these compounds sufficiently elucidated so far. We looked for the effects of chronic NOS possess a number of biological effects including anti-aggregatory inhibition by L-NAME treatment on the modulation of ischemic platelet activity, antioxidant and free radical scavenging properties.
    [Show full text]