Endothelial Nitric Oxide Synthase Uncoupling Impairs Endothelial Progenitor Cell Mobilization and Function in Diabetes
Endothelial Nitric Oxide Synthase Uncoupling Impairs Endothelial Progenitor Cell Mobilization and Function in Diabetes Thomas Thum 1 , Daniela Fraccarollo 1 , Maximilian Schultheiss 1 , Sabrina Froese 1 , Paolo Galuppo 1 , Julian D. Widder 1 2 , Dimitrios Tsikas 3 , Georg Ertl 1 and Johann Bauersach...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2007-03, Vol.56 (3), p.666-674 |
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| creator | THUM, Thomas FRACCAROLLO, Daniela SCHULTHEISS, Maximilian FROESE, Sabrina GALUPPO, Paolo WIDDER, Julian D TSIKAS, Dimitrios ERTL, Georg BAUERSACHS, Johann |
| description | Endothelial Nitric Oxide Synthase Uncoupling Impairs Endothelial Progenitor Cell Mobilization and Function in Diabetes
Thomas Thum 1 ,
Daniela Fraccarollo 1 ,
Maximilian Schultheiss 1 ,
Sabrina Froese 1 ,
Paolo Galuppo 1 ,
Julian D. Widder 1 2 ,
Dimitrios Tsikas 3 ,
Georg Ertl 1 and
Johann Bauersachs 1
1 Universität Würzburg, Universitatsklinikum, Medizinische Klinik I, Würzburg, Germany
2 Division of Cardiology, Emory School of Medicine, Atlanta, Georgia
3 Institute for Clinical Pharmacology, Medical School Hannover, Hannover, Germany
Address correspondence and reprint requests to Dr. med. Thomas Thum or PD Dr. med. Johann Bauersachs, Universitatsklinikum,
Medizinische Klinik I, Josef-Schneider Str. 2, 97080 Würzburg, Germany. E-mail: thum_t{at}klinik.uni-wuerzburg.de or bauersachs_j{at}medizin.uni-wuerzburg.de
Abstract
Uncoupling of the endothelial nitric oxide synthase (eNOS) resulting in superoxide anion (O 2 − ) formation instead of nitric oxide (NO) causes diabetic endothelial dysfunction. eNOS regulates mobilization and function
of endothelial progenitor cells (EPCs), key regulators of vascular repair. We postulate a role of eNOS uncoupling for reduced
number and function of EPC in diabetes. EPC levels in diabetic patients were significantly reduced compared with those of
control subjects. EPCs from diabetic patients produced excessive O 2 − and showed impaired migratory capacity compared with nondiabetic control subjects. NOS inhibition with N G -nitro- l -arginine attenuated O 2 − production and normalized functional capacity of EPCs from diabetic patients. Glucose-mediated EPC dysfunction was protein
kinase C dependent, associated with reduced intracellular BH 4 (tetrahydrobiopterin) concentrations, and reversible after exogenous BH 4 treatment. Activation of NADPH oxidases played an additional but minor role in glucose-mediated EPC dysfunction. In rats
with streptozotocin-induced diabetes, circulating EPCs were reduced to 39 ± 5% of controls and associated with uncoupled eNOS
in bone marrow. Our results identify uncoupling of eNOS in diabetic bone marrow, glucose-treated EPCs, and EPCs from diabetic
patients resulting in eNOS-mediated O 2 − production. Subsequent reduction of EPC levels and impairment of EPC function likely contributes to the pathogenesis of vascular
disease in diabetes.
BH4, tetrahydrobiopterin
CFU, colony forming unit
EBM, endothelial basal medium
eNOS, endothelial nitric oxide synthase
EPC, endothelial progenitor cell
HPLC, h |
| doi_str_mv | 10.2337/db06-0699 |
| format | Article |
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Thomas Thum 1 ,
Daniela Fraccarollo 1 ,
Maximilian Schultheiss 1 ,
Sabrina Froese 1 ,
Paolo Galuppo 1 ,
Julian D. Widder 1 2 ,
Dimitrios Tsikas 3 ,
Georg Ertl 1 and
Johann Bauersachs 1
1 Universität Würzburg, Universitatsklinikum, Medizinische Klinik I, Würzburg, Germany
2 Division of Cardiology, Emory School of Medicine, Atlanta, Georgia
3 Institute for Clinical Pharmacology, Medical School Hannover, Hannover, Germany
Address correspondence and reprint requests to Dr. med. Thomas Thum or PD Dr. med. Johann Bauersachs, Universitatsklinikum,
Medizinische Klinik I, Josef-Schneider Str. 2, 97080 Würzburg, Germany. E-mail: thum_t{at}klinik.uni-wuerzburg.de or bauersachs_j{at}medizin.uni-wuerzburg.de
Abstract
Uncoupling of the endothelial nitric oxide synthase (eNOS) resulting in superoxide anion (O 2 − ) formation instead of nitric oxide (NO) causes diabetic endothelial dysfunction. eNOS regulates mobilization and function
of endothelial progenitor cells (EPCs), key regulators of vascular repair. We postulate a role of eNOS uncoupling for reduced
number and function of EPC in diabetes. EPC levels in diabetic patients were significantly reduced compared with those of
control subjects. EPCs from diabetic patients produced excessive O 2 − and showed impaired migratory capacity compared with nondiabetic control subjects. NOS inhibition with N G -nitro- l -arginine attenuated O 2 − production and normalized functional capacity of EPCs from diabetic patients. Glucose-mediated EPC dysfunction was protein
kinase C dependent, associated with reduced intracellular BH 4 (tetrahydrobiopterin) concentrations, and reversible after exogenous BH 4 treatment. Activation of NADPH oxidases played an additional but minor role in glucose-mediated EPC dysfunction. In rats
with streptozotocin-induced diabetes, circulating EPCs were reduced to 39 ± 5% of controls and associated with uncoupled eNOS
in bone marrow. Our results identify uncoupling of eNOS in diabetic bone marrow, glucose-treated EPCs, and EPCs from diabetic
patients resulting in eNOS-mediated O 2 − production. Subsequent reduction of EPC levels and impairment of EPC function likely contributes to the pathogenesis of vascular
disease in diabetes.
BH4, tetrahydrobiopterin
CFU, colony forming unit
EBM, endothelial basal medium
eNOS, endothelial nitric oxide synthase
EPC, endothelial progenitor cell
HPLC, high-performance liquid chromatography
l-NNA, NG-nitro-l-arginine
PBMC, peripheral blood mononuclear cell
PKC, protein kinase C
ROS, reactive oxygen species
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted December 12, 2006.
Received May 22, 2006.
DIABETES</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db06-0699</identifier><identifier>PMID: 17327434</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>Alexandria, VA: American Diabetes Association</publisher><subject>Aged ; Animals ; Biological and medical sciences ; Biopterins - analogs & derivatives ; Biopterins - pharmacology ; Bone marrow ; Bone Marrow - metabolism ; Cardiovascular disease ; Cardiovascular diseases ; Care and treatment ; Cell Movement - physiology ; Cells, Cultured ; Complications and side effects ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Experimental - enzymology ; Diabetes Mellitus, Experimental - pathology ; Diabetes. Impaired glucose tolerance ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Endothelial Cells - drug effects ; Endothelial Cells - enzymology ; Endothelial Cells - pathology ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Female ; Glucose ; Humans ; Kinases ; Laboratory animals ; Male ; Medical sciences ; Nitric oxide ; Nitric Oxide Synthase Type III - metabolism ; Nitroarginine - pharmacology ; Pathogenesis ; Patients ; Protein Kinase C - metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species - metabolism ; Risk factors ; Stem Cells - drug effects ; Stem Cells - enzymology ; Stem Cells - pathology</subject><ispartof>Diabetes (New York, N.Y.), 2007-03, Vol.56 (3), p.666-674</ispartof><rights>2007 INIST-CNRS</rights><rights>COPYRIGHT 2007 American Diabetes Association</rights><rights>Copyright American Diabetes Association Mar 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c559t-5e6a4c2fc46ca6e32cf2cb80b042079bbe5439e3014b6641b6c9e7f903f2019f3</citedby><cites>FETCH-LOGICAL-c559t-5e6a4c2fc46ca6e32cf2cb80b042079bbe5439e3014b6641b6c9e7f903f2019f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18592535$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17327434$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>THUM, Thomas</creatorcontrib><creatorcontrib>FRACCAROLLO, Daniela</creatorcontrib><creatorcontrib>SCHULTHEISS, Maximilian</creatorcontrib><creatorcontrib>FROESE, Sabrina</creatorcontrib><creatorcontrib>GALUPPO, Paolo</creatorcontrib><creatorcontrib>WIDDER, Julian D</creatorcontrib><creatorcontrib>TSIKAS, Dimitrios</creatorcontrib><creatorcontrib>ERTL, Georg</creatorcontrib><creatorcontrib>BAUERSACHS, Johann</creatorcontrib><title>Endothelial Nitric Oxide Synthase Uncoupling Impairs Endothelial Progenitor Cell Mobilization and Function in Diabetes</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Endothelial Nitric Oxide Synthase Uncoupling Impairs Endothelial Progenitor Cell Mobilization and Function in Diabetes
Thomas Thum 1 ,
Daniela Fraccarollo 1 ,
Maximilian Schultheiss 1 ,
Sabrina Froese 1 ,
Paolo Galuppo 1 ,
Julian D. Widder 1 2 ,
Dimitrios Tsikas 3 ,
Georg Ertl 1 and
Johann Bauersachs 1
1 Universität Würzburg, Universitatsklinikum, Medizinische Klinik I, Würzburg, Germany
2 Division of Cardiology, Emory School of Medicine, Atlanta, Georgia
3 Institute for Clinical Pharmacology, Medical School Hannover, Hannover, Germany
Address correspondence and reprint requests to Dr. med. Thomas Thum or PD Dr. med. Johann Bauersachs, Universitatsklinikum,
Medizinische Klinik I, Josef-Schneider Str. 2, 97080 Würzburg, Germany. E-mail: thum_t{at}klinik.uni-wuerzburg.de or bauersachs_j{at}medizin.uni-wuerzburg.de
Abstract
Uncoupling of the endothelial nitric oxide synthase (eNOS) resulting in superoxide anion (O 2 − ) formation instead of nitric oxide (NO) causes diabetic endothelial dysfunction. eNOS regulates mobilization and function
of endothelial progenitor cells (EPCs), key regulators of vascular repair. We postulate a role of eNOS uncoupling for reduced
number and function of EPC in diabetes. EPC levels in diabetic patients were significantly reduced compared with those of
control subjects. EPCs from diabetic patients produced excessive O 2 − and showed impaired migratory capacity compared with nondiabetic control subjects. NOS inhibition with N G -nitro- l -arginine attenuated O 2 − production and normalized functional capacity of EPCs from diabetic patients. Glucose-mediated EPC dysfunction was protein
kinase C dependent, associated with reduced intracellular BH 4 (tetrahydrobiopterin) concentrations, and reversible after exogenous BH 4 treatment. Activation of NADPH oxidases played an additional but minor role in glucose-mediated EPC dysfunction. In rats
with streptozotocin-induced diabetes, circulating EPCs were reduced to 39 ± 5% of controls and associated with uncoupled eNOS
in bone marrow. Our results identify uncoupling of eNOS in diabetic bone marrow, glucose-treated EPCs, and EPCs from diabetic
patients resulting in eNOS-mediated O 2 − production. Subsequent reduction of EPC levels and impairment of EPC function likely contributes to the pathogenesis of vascular
disease in diabetes.
BH4, tetrahydrobiopterin
CFU, colony forming unit
EBM, endothelial basal medium
eNOS, endothelial nitric oxide synthase
EPC, endothelial progenitor cell
HPLC, high-performance liquid chromatography
l-NNA, NG-nitro-l-arginine
PBMC, peripheral blood mononuclear cell
PKC, protein kinase C
ROS, reactive oxygen species
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted December 12, 2006.
Received May 22, 2006.
DIABETES</description><subject>Aged</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Biopterins - analogs & derivatives</subject><subject>Biopterins - pharmacology</subject><subject>Bone marrow</subject><subject>Bone Marrow - metabolism</subject><subject>Cardiovascular disease</subject><subject>Cardiovascular diseases</subject><subject>Care and treatment</subject><subject>Cell Movement - physiology</subject><subject>Cells, Cultured</subject><subject>Complications and side effects</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Experimental - enzymology</subject><subject>Diabetes Mellitus, Experimental - pathology</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Endothelial Cells - drug effects</subject><subject>Endothelial Cells - enzymology</subject><subject>Endothelial Cells - pathology</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Female</subject><subject>Glucose</subject><subject>Humans</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Nitric oxide</subject><subject>Nitric Oxide Synthase Type III - metabolism</subject><subject>Nitroarginine - pharmacology</subject><subject>Pathogenesis</subject><subject>Patients</subject><subject>Protein Kinase C - metabolism</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Risk factors</subject><subject>Stem Cells - drug effects</subject><subject>Stem Cells - enzymology</subject><subject>Stem Cells - pathology</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpt0l2L1DAUBuAiijuuXvgHJAgKLnTNR5tOLpdxv2B0BF3wLqTpaSdLJhmTVHf99WZ2BsaVIRdtynNO0sNbFK8JPqWMNR-7FvMScyGeFBMimCgZbX48LSYYE1qSRjRHxYsYbzHGPK_nxRFpsqhYNSl-nbvOpyVYoyz6YlIwGi3uTAfo271LSxUB3Tjtx7U1bkDXq7UyIaJ_i74GP4AzyQc0A2vRZ98aa_6oZLxDynXoYnT6YWMc-mRUCwniy-JZr2yEV7vncXFzcf59dlXOF5fXs7N5qetapLIGripNe11xrTgwqnuq2ylucUVxI9oW6ooJYJhULecVabkW0PQCs55iInp2XLzf9l0H_3OEmOTKRJ2vqRz4McoG0zwfVmf49j9468fg8t0kJbwSlFCaUblFg7Igjet9Ckrnv4egrHfQm_z5jHBcC1rXJPvTAz6vDlZGHyz48KggmwR3aVBjjHJ6OX9sy0NWe2thAJnHOFsc7K2DjzFAL9fBrFS4lwTLTYzkJkZyE6Ns3-ymMbYr6PZyl5sM3u2AilrZPiinTdy76ebQh7GebN3SDMvfJoDsdgnYv9RcMsk5Z38BBCLb5w</recordid><startdate>20070301</startdate><enddate>20070301</enddate><creator>THUM, Thomas</creator><creator>FRACCAROLLO, Daniela</creator><creator>SCHULTHEISS, Maximilian</creator><creator>FROESE, Sabrina</creator><creator>GALUPPO, Paolo</creator><creator>WIDDER, Julian D</creator><creator>TSIKAS, Dimitrios</creator><creator>ERTL, Georg</creator><creator>BAUERSACHS, Johann</creator><general>American Diabetes Association</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8GL</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7P</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>S0X</scope><scope>7X8</scope></search><sort><creationdate>20070301</creationdate><title>Endothelial Nitric Oxide Synthase Uncoupling Impairs Endothelial Progenitor Cell Mobilization and Function in Diabetes</title><author>THUM, Thomas ; FRACCAROLLO, Daniela ; SCHULTHEISS, Maximilian ; FROESE, Sabrina ; GALUPPO, Paolo ; WIDDER, Julian D ; TSIKAS, Dimitrios ; ERTL, Georg ; BAUERSACHS, Johann</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c559t-5e6a4c2fc46ca6e32cf2cb80b042079bbe5439e3014b6641b6c9e7f903f2019f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Aged</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Biopterins - analogs & derivatives</topic><topic>Biopterins - pharmacology</topic><topic>Bone marrow</topic><topic>Bone Marrow - metabolism</topic><topic>Cardiovascular disease</topic><topic>Cardiovascular diseases</topic><topic>Care and treatment</topic><topic>Cell Movement - physiology</topic><topic>Cells, Cultured</topic><topic>Complications and side effects</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Experimental - enzymology</topic><topic>Diabetes Mellitus, Experimental - pathology</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Endothelial Cells - drug effects</topic><topic>Endothelial Cells - enzymology</topic><topic>Endothelial Cells - pathology</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Female</topic><topic>Glucose</topic><topic>Humans</topic><topic>Kinases</topic><topic>Laboratory animals</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Nitric oxide</topic><topic>Nitric Oxide Synthase Type III - metabolism</topic><topic>Nitroarginine - pharmacology</topic><topic>Pathogenesis</topic><topic>Patients</topic><topic>Protein Kinase C - metabolism</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Risk factors</topic><topic>Stem Cells - drug effects</topic><topic>Stem Cells - enzymology</topic><topic>Stem Cells - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>THUM, Thomas</creatorcontrib><creatorcontrib>FRACCAROLLO, Daniela</creatorcontrib><creatorcontrib>SCHULTHEISS, Maximilian</creatorcontrib><creatorcontrib>FROESE, Sabrina</creatorcontrib><creatorcontrib>GALUPPO, Paolo</creatorcontrib><creatorcontrib>WIDDER, Julian D</creatorcontrib><creatorcontrib>TSIKAS, Dimitrios</creatorcontrib><creatorcontrib>ERTL, Georg</creatorcontrib><creatorcontrib>BAUERSACHS, Johann</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: High School</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>THUM, Thomas</au><au>FRACCAROLLO, Daniela</au><au>SCHULTHEISS, Maximilian</au><au>FROESE, Sabrina</au><au>GALUPPO, Paolo</au><au>WIDDER, Julian D</au><au>TSIKAS, Dimitrios</au><au>ERTL, Georg</au><au>BAUERSACHS, Johann</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Endothelial Nitric Oxide Synthase Uncoupling Impairs Endothelial Progenitor Cell Mobilization and Function in Diabetes</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2007-03-01</date><risdate>2007</risdate><volume>56</volume><issue>3</issue><spage>666</spage><epage>674</epage><pages>666-674</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Endothelial Nitric Oxide Synthase Uncoupling Impairs Endothelial Progenitor Cell Mobilization and Function in Diabetes
Thomas Thum 1 ,
Daniela Fraccarollo 1 ,
Maximilian Schultheiss 1 ,
Sabrina Froese 1 ,
Paolo Galuppo 1 ,
Julian D. Widder 1 2 ,
Dimitrios Tsikas 3 ,
Georg Ertl 1 and
Johann Bauersachs 1
1 Universität Würzburg, Universitatsklinikum, Medizinische Klinik I, Würzburg, Germany
2 Division of Cardiology, Emory School of Medicine, Atlanta, Georgia
3 Institute for Clinical Pharmacology, Medical School Hannover, Hannover, Germany
Address correspondence and reprint requests to Dr. med. Thomas Thum or PD Dr. med. Johann Bauersachs, Universitatsklinikum,
Medizinische Klinik I, Josef-Schneider Str. 2, 97080 Würzburg, Germany. E-mail: thum_t{at}klinik.uni-wuerzburg.de or bauersachs_j{at}medizin.uni-wuerzburg.de
Abstract
Uncoupling of the endothelial nitric oxide synthase (eNOS) resulting in superoxide anion (O 2 − ) formation instead of nitric oxide (NO) causes diabetic endothelial dysfunction. eNOS regulates mobilization and function
of endothelial progenitor cells (EPCs), key regulators of vascular repair. We postulate a role of eNOS uncoupling for reduced
number and function of EPC in diabetes. EPC levels in diabetic patients were significantly reduced compared with those of
control subjects. EPCs from diabetic patients produced excessive O 2 − and showed impaired migratory capacity compared with nondiabetic control subjects. NOS inhibition with N G -nitro- l -arginine attenuated O 2 − production and normalized functional capacity of EPCs from diabetic patients. Glucose-mediated EPC dysfunction was protein
kinase C dependent, associated with reduced intracellular BH 4 (tetrahydrobiopterin) concentrations, and reversible after exogenous BH 4 treatment. Activation of NADPH oxidases played an additional but minor role in glucose-mediated EPC dysfunction. In rats
with streptozotocin-induced diabetes, circulating EPCs were reduced to 39 ± 5% of controls and associated with uncoupled eNOS
in bone marrow. Our results identify uncoupling of eNOS in diabetic bone marrow, glucose-treated EPCs, and EPCs from diabetic
patients resulting in eNOS-mediated O 2 − production. Subsequent reduction of EPC levels and impairment of EPC function likely contributes to the pathogenesis of vascular
disease in diabetes.
BH4, tetrahydrobiopterin
CFU, colony forming unit
EBM, endothelial basal medium
eNOS, endothelial nitric oxide synthase
EPC, endothelial progenitor cell
HPLC, high-performance liquid chromatography
l-NNA, NG-nitro-l-arginine
PBMC, peripheral blood mononuclear cell
PKC, protein kinase C
ROS, reactive oxygen species
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted December 12, 2006.
Received May 22, 2006.
DIABETES</abstract><cop>Alexandria, VA</cop><pub>American Diabetes Association</pub><pmid>17327434</pmid><doi>10.2337/db06-0699</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0012-1797 |
| ispartof | Diabetes (New York, N.Y.), 2007-03, Vol.56 (3), p.666-674 |
| issn | 0012-1797 1939-327X |
| language | eng |
| recordid | cdi_pubmed_primary_17327434 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Aged Animals Biological and medical sciences Biopterins - analogs & derivatives Biopterins - pharmacology Bone marrow Bone Marrow - metabolism Cardiovascular disease Cardiovascular diseases Care and treatment Cell Movement - physiology Cells, Cultured Complications and side effects Diabetes Diabetes mellitus Diabetes Mellitus, Experimental - enzymology Diabetes Mellitus, Experimental - pathology Diabetes. Impaired glucose tolerance Endocrine pancreas. Apud cells (diseases) Endocrinopathies Endothelial Cells - drug effects Endothelial Cells - enzymology Endothelial Cells - pathology Etiopathogenesis. Screening. Investigations. Target tissue resistance Female Glucose Humans Kinases Laboratory animals Male Medical sciences Nitric oxide Nitric Oxide Synthase Type III - metabolism Nitroarginine - pharmacology Pathogenesis Patients Protein Kinase C - metabolism Rats Rats, Wistar Reactive Oxygen Species - metabolism Risk factors Stem Cells - drug effects Stem Cells - enzymology Stem Cells - pathology |
| title | Endothelial Nitric Oxide Synthase Uncoupling Impairs Endothelial Progenitor Cell Mobilization and Function in Diabetes |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T06%3A40%3A28IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Endothelial%20Nitric%20Oxide%20Synthase%20Uncoupling%20Impairs%20Endothelial%20Progenitor%20Cell%20Mobilization%20and%20Function%20in%20Diabetes&rft.jtitle=Diabetes%20(New%20York,%20N.Y.)&rft.au=THUM,%20Thomas&rft.date=2007-03-01&rft.volume=56&rft.issue=3&rft.spage=666&rft.epage=674&rft.pages=666-674&rft.issn=0012-1797&rft.eissn=1939-327X&rft.coden=DIAEAZ&rft_id=info:doi/10.2337/db06-0699&rft_dat=%3Cgale_pubme%3EA160592551%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=216492122&rft_id=info:pmid/17327434&rft_galeid=A160592551&rfr_iscdi=true |