Role of ROCK upregulation in endothelial and smooth muscle vascular functions in diabetic rat aorta
The RhoA/ROCK signaling pathway mediates vascular smooth muscle contraction while endogenous NO induces vasodilation through its inhibition. Since myosin light chain phosphatase (MLCP) and eNOS are targeted by RhoA/ROCK upregulation then turn to lead abnormalities in vasculature, we aimed to examine...
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| Veröffentlicht in: | Cardiovascular Diabetology 2013-03, Vol.12 (1), p.51-51, Article 51 |
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| creator | Cicek, Figen Amber Kandilci, Hilmi B Turan, Belma |
| description | The RhoA/ROCK signaling pathway mediates vascular smooth muscle contraction while endogenous NO induces vasodilation through its inhibition. Since myosin light chain phosphatase (MLCP) and eNOS are targeted by RhoA/ROCK upregulation then turn to lead abnormalities in vasculature, we aimed to examine whether less endothelial NO-production and inhibited eNOS together with an upregulation of RhoA/ROCK signaling pathway in thoracic aorta can play an important role in vascular dysfunction under hyperglycemia.
We used streptozotocin-injected rats, as a model of type 1 diabetes, and their lean controls to investigate the role of ROCK upregulation in the function of toracic aorta by using electrophysiological and biochemical techniques.
The protein level of ROCK isoform ROCK2 was found to be 2.5-fold higher in endothelium-intact aortic rings of the diabetic rats compared to those of the controls while its level in endothelium-denuded rings was similar among these two groups. Phosphorylation level of eNOS in endothelium-intact rings from the diabetics was 50% less compared to that of the control. ROCK inhibitors, either Y27632 or HA1077, induced concentration-dependent relaxation with a marked left-shift in phenylephrine pre-contracted endothelium-intact rings from either diabetics or high glucose incubated controls while pretreatment of these rings with L-NAME abolished this shift, fully. Moreover, phosphorylation levels of both MLCP and MLC in endothelium-denuded rings were markedly higher in the diabetics than the controls.
We demonstrated that diabetes-induced vascular dysfunction can arise due to either inbition of eNOS, thereby less endothelial NO-production, either directly or indirectly, in part, due to an upregulation of ROCK2 by hyperglycemia. Additionally, our data demonstrate that high phosphorylation levels of both MLC and MLCP in endothelium-denuded rings can be due to a less endothelial NO-production dependent ROCK upregulation in the smooth muscle cells under hyperglycemia, as well. |
| doi_str_mv | 10.1186/1475-2840-12-51 |
| format | Article |
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We used streptozotocin-injected rats, as a model of type 1 diabetes, and their lean controls to investigate the role of ROCK upregulation in the function of toracic aorta by using electrophysiological and biochemical techniques.
The protein level of ROCK isoform ROCK2 was found to be 2.5-fold higher in endothelium-intact aortic rings of the diabetic rats compared to those of the controls while its level in endothelium-denuded rings was similar among these two groups. Phosphorylation level of eNOS in endothelium-intact rings from the diabetics was 50% less compared to that of the control. ROCK inhibitors, either Y27632 or HA1077, induced concentration-dependent relaxation with a marked left-shift in phenylephrine pre-contracted endothelium-intact rings from either diabetics or high glucose incubated controls while pretreatment of these rings with L-NAME abolished this shift, fully. Moreover, phosphorylation levels of both MLCP and MLC in endothelium-denuded rings were markedly higher in the diabetics than the controls.
We demonstrated that diabetes-induced vascular dysfunction can arise due to either inbition of eNOS, thereby less endothelial NO-production, either directly or indirectly, in part, due to an upregulation of ROCK2 by hyperglycemia. Additionally, our data demonstrate that high phosphorylation levels of both MLC and MLCP in endothelium-denuded rings can be due to a less endothelial NO-production dependent ROCK upregulation in the smooth muscle cells under hyperglycemia, as well.</description><identifier>ISSN: 1475-2840</identifier><identifier>EISSN: 1475-2840</identifier><identifier>DOI: 10.1186/1475-2840-12-51</identifier><identifier>PMID: 23530857</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>Animals ; Aorta, Thoracic - enzymology ; Care and treatment ; Cells ; Diabetes Mellitus, Experimental - enzymology ; Diabetes therapy ; Endothelium ; Endothelium, Vascular - enzymology ; Hyperglycemia ; Male ; Muscle proteins ; Muscle, Smooth, Vascular - enzymology ; Muscular system ; Myosin ; Nitric oxide ; Original Investigation ; Phosphatases ; Prognosis ; Proteins ; Rats ; Rats, Wistar ; rho-Associated Kinases - physiology ; Risk factors ; Rodents ; Smooth muscle ; Streptozocin ; Type 1 diabetes ; Up-Regulation - physiology</subject><ispartof>Cardiovascular Diabetology, 2013-03, Vol.12 (1), p.51-51, Article 51</ispartof><rights>COPYRIGHT 2013 BioMed Central Ltd.</rights><rights>2013 Cicek et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</rights><rights>Copyright © 2013 Cicek et al.; licensee BioMed Central Ltd. 2013 Cicek et al.; licensee BioMed Central Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b613t-24ca477024afe0856b1f8ad9bb77c20709da807e85a8c5f70c5da6c15f8a40013</citedby><cites>FETCH-LOGICAL-b613t-24ca477024afe0856b1f8ad9bb77c20709da807e85a8c5f70c5da6c15f8a40013</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620917/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620917/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23530857$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cicek, Figen Amber</creatorcontrib><creatorcontrib>Kandilci, Hilmi B</creatorcontrib><creatorcontrib>Turan, Belma</creatorcontrib><title>Role of ROCK upregulation in endothelial and smooth muscle vascular functions in diabetic rat aorta</title><title>Cardiovascular Diabetology</title><addtitle>Cardiovasc Diabetol</addtitle><description>The RhoA/ROCK signaling pathway mediates vascular smooth muscle contraction while endogenous NO induces vasodilation through its inhibition. Since myosin light chain phosphatase (MLCP) and eNOS are targeted by RhoA/ROCK upregulation then turn to lead abnormalities in vasculature, we aimed to examine whether less endothelial NO-production and inhibited eNOS together with an upregulation of RhoA/ROCK signaling pathway in thoracic aorta can play an important role in vascular dysfunction under hyperglycemia.
We used streptozotocin-injected rats, as a model of type 1 diabetes, and their lean controls to investigate the role of ROCK upregulation in the function of toracic aorta by using electrophysiological and biochemical techniques.
The protein level of ROCK isoform ROCK2 was found to be 2.5-fold higher in endothelium-intact aortic rings of the diabetic rats compared to those of the controls while its level in endothelium-denuded rings was similar among these two groups. Phosphorylation level of eNOS in endothelium-intact rings from the diabetics was 50% less compared to that of the control. ROCK inhibitors, either Y27632 or HA1077, induced concentration-dependent relaxation with a marked left-shift in phenylephrine pre-contracted endothelium-intact rings from either diabetics or high glucose incubated controls while pretreatment of these rings with L-NAME abolished this shift, fully. Moreover, phosphorylation levels of both MLCP and MLC in endothelium-denuded rings were markedly higher in the diabetics than the controls.
We demonstrated that diabetes-induced vascular dysfunction can arise due to either inbition of eNOS, thereby less endothelial NO-production, either directly or indirectly, in part, due to an upregulation of ROCK2 by hyperglycemia. Additionally, our data demonstrate that high phosphorylation levels of both MLC and MLCP in endothelium-denuded rings can be due to a less endothelial NO-production dependent ROCK upregulation in the smooth muscle cells under hyperglycemia, as well.</description><subject>Animals</subject><subject>Aorta, Thoracic - enzymology</subject><subject>Care and treatment</subject><subject>Cells</subject><subject>Diabetes Mellitus, Experimental - enzymology</subject><subject>Diabetes therapy</subject><subject>Endothelium</subject><subject>Endothelium, Vascular - enzymology</subject><subject>Hyperglycemia</subject><subject>Male</subject><subject>Muscle proteins</subject><subject>Muscle, Smooth, Vascular - enzymology</subject><subject>Muscular system</subject><subject>Myosin</subject><subject>Nitric oxide</subject><subject>Original Investigation</subject><subject>Phosphatases</subject><subject>Prognosis</subject><subject>Proteins</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>rho-Associated Kinases - physiology</subject><subject>Risk factors</subject><subject>Rodents</subject><subject>Smooth muscle</subject><subject>Streptozocin</subject><subject>Type 1 diabetes</subject><subject>Up-Regulation - physiology</subject><issn>1475-2840</issn><issn>1475-2840</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1Uk1rFTEUDaLYD127k4AbN9PmczKzEepDq1goFF2HO5nkNSWTPJOZgv_eDK8-WlGySHLvOSfnHoLQG0rOKO3acyqUbFgnSENZI-kzdHyoPH90PkInpdwRQlXX0pfoiHHJSSfVMTI3KVicHL653nzDyy7b7RJg9iliH7GNY5pvbfAQMMQRlynVO56WYirrHoqp4IzdEs1KKStn9DDY2RucYcaQ8gyv0AsHodjXD_sp-vH50_fNl-bq-vLr5uKqGVrK54YJA0IpwgQ4W921A3UdjP0wKGUYUaQfoSPKdhI6I50iRo7QGiorStTZ-Cn6sNfdLcNkR2PjnCHoXfYT5F86gddPO9Hf6m2617xlpKeqCnzcCww-_UfgacekSa8h6zVkTZmWq4v3Dy5y-rnYMuvJF2NDgGjTUjTlTHJORN9X6Lu_oHdpybFmtKKEIJQqVlFne9QWgtU-ulTfNnWNdvImRet8rV9ILlpJpVjHON8TTE6lZOsOE9Bqsn6bf3h--zi5A_7PP-G_Adbkvi0</recordid><startdate>20130327</startdate><enddate>20130327</enddate><creator>Cicek, Figen Amber</creator><creator>Kandilci, Hilmi B</creator><creator>Turan, Belma</creator><general>BioMed Central Ltd</general><general>BioMed Central</general><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>IAO</scope><scope>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130327</creationdate><title>Role of ROCK upregulation in endothelial and smooth muscle vascular functions in diabetic rat aorta</title><author>Cicek, Figen Amber ; Kandilci, Hilmi B ; Turan, Belma</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b613t-24ca477024afe0856b1f8ad9bb77c20709da807e85a8c5f70c5da6c15f8a40013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Aorta, Thoracic - enzymology</topic><topic>Care and treatment</topic><topic>Cells</topic><topic>Diabetes Mellitus, Experimental - enzymology</topic><topic>Diabetes therapy</topic><topic>Endothelium</topic><topic>Endothelium, Vascular - enzymology</topic><topic>Hyperglycemia</topic><topic>Male</topic><topic>Muscle proteins</topic><topic>Muscle, Smooth, Vascular - enzymology</topic><topic>Muscular system</topic><topic>Myosin</topic><topic>Nitric oxide</topic><topic>Original Investigation</topic><topic>Phosphatases</topic><topic>Prognosis</topic><topic>Proteins</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>rho-Associated Kinases - physiology</topic><topic>Risk factors</topic><topic>Rodents</topic><topic>Smooth muscle</topic><topic>Streptozocin</topic><topic>Type 1 diabetes</topic><topic>Up-Regulation - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cicek, Figen Amber</creatorcontrib><creatorcontrib>Kandilci, Hilmi B</creatorcontrib><creatorcontrib>Turan, Belma</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale Academic OneFile</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>ProQuest Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Publicly Available Content Database</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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cardiovascular Diabetology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cicek, Figen Amber</au><au>Kandilci, Hilmi B</au><au>Turan, Belma</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role of ROCK upregulation in endothelial and smooth muscle vascular functions in diabetic rat aorta</atitle><jtitle>Cardiovascular Diabetology</jtitle><addtitle>Cardiovasc Diabetol</addtitle><date>2013-03-27</date><risdate>2013</risdate><volume>12</volume><issue>1</issue><spage>51</spage><epage>51</epage><pages>51-51</pages><artnum>51</artnum><issn>1475-2840</issn><eissn>1475-2840</eissn><abstract>The RhoA/ROCK signaling pathway mediates vascular smooth muscle contraction while endogenous NO induces vasodilation through its inhibition. Since myosin light chain phosphatase (MLCP) and eNOS are targeted by RhoA/ROCK upregulation then turn to lead abnormalities in vasculature, we aimed to examine whether less endothelial NO-production and inhibited eNOS together with an upregulation of RhoA/ROCK signaling pathway in thoracic aorta can play an important role in vascular dysfunction under hyperglycemia.
We used streptozotocin-injected rats, as a model of type 1 diabetes, and their lean controls to investigate the role of ROCK upregulation in the function of toracic aorta by using electrophysiological and biochemical techniques.
The protein level of ROCK isoform ROCK2 was found to be 2.5-fold higher in endothelium-intact aortic rings of the diabetic rats compared to those of the controls while its level in endothelium-denuded rings was similar among these two groups. Phosphorylation level of eNOS in endothelium-intact rings from the diabetics was 50% less compared to that of the control. ROCK inhibitors, either Y27632 or HA1077, induced concentration-dependent relaxation with a marked left-shift in phenylephrine pre-contracted endothelium-intact rings from either diabetics or high glucose incubated controls while pretreatment of these rings with L-NAME abolished this shift, fully. Moreover, phosphorylation levels of both MLCP and MLC in endothelium-denuded rings were markedly higher in the diabetics than the controls.
We demonstrated that diabetes-induced vascular dysfunction can arise due to either inbition of eNOS, thereby less endothelial NO-production, either directly or indirectly, in part, due to an upregulation of ROCK2 by hyperglycemia. Additionally, our data demonstrate that high phosphorylation levels of both MLC and MLCP in endothelium-denuded rings can be due to a less endothelial NO-production dependent ROCK upregulation in the smooth muscle cells under hyperglycemia, as well.</abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>23530857</pmid><doi>10.1186/1475-2840-12-51</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Aorta, Thoracic - enzymology Care and treatment Cells Diabetes Mellitus, Experimental - enzymology Diabetes therapy Endothelium Endothelium, Vascular - enzymology Hyperglycemia Male Muscle proteins Muscle, Smooth, Vascular - enzymology Muscular system Myosin Nitric oxide Original Investigation Phosphatases Prognosis Proteins Rats Rats, Wistar rho-Associated Kinases - physiology Risk factors Rodents Smooth muscle Streptozocin Type 1 diabetes Up-Regulation - physiology |
| title | Role of ROCK upregulation in endothelial and smooth muscle vascular functions in diabetic rat aorta |
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