A Novel Role of Irbesartan in Gastroprotection against Indomethacin-Induced Gastric Injury in Rats: Targeting DDAH/ADMA and EGFR/ERK Signaling
The advent of angiotensin II type 1 receptor blockers (ARBs) as intriguing gastroprotective candidates and the superior pharmacokinetics and pharmacodynamics displayed by irbesartan compared to many other ARBs raised the interest to investigate its gastroprotective potential in a rat model of gastri...
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| description | The advent of angiotensin II type 1 receptor blockers (ARBs) as intriguing gastroprotective candidates and the superior pharmacokinetics and pharmacodynamics displayed by irbesartan compared to many other ARBs raised the interest to investigate its gastroprotective potential in a rat model of gastric injury. Irbesartan (50 mg/Kg) was orally administered to male Wistar rats once daily for 14 days; thereafter gastric injury was induced by indomethacin (60 mg/Kg, p.o). Irbesartan reduced gastric ulcer index, gastric acidity, and ameliorated indomethacin-induced gastric mucosal apoptotic and inflammatory aberrations, as demonstrated by hampering caspase-3, prostaglandin E
2
and tumor necrosis factor-alpha levels and cyclooxygenase-2 mRNA expression. This ARB increased mucosal dimethylarginine dimethylaminohydrolase-1 (DDAH-1) gene expression and decreased elevated levels of matrix metalloproteinase-9, asymmetric dimethylarginine (ADMA), epidermal growth factor receptor (EGFR) mRNA and phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2). Histopathological evaluation corroborated biochemical findings. Overall efficacy of irbesartan was comparable to ranitidine, the widely used H
2
receptor blocker. In conclusion, irbesartan exerts significant gastroprotection against indomethacin-induced mucosal damage via acid-inhibitory, anti-inflammatory, anti-apoptotic and extracellular matrix remodeling mechanisms that are probably mediated, at least partly, by down-regulating DDAH/ADMA and EGFR/ERK1/2 signaling. |
| doi_str_mv | 10.1038/s41598-018-22727-6 |
| format | Article |
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2
and tumor necrosis factor-alpha levels and cyclooxygenase-2 mRNA expression. This ARB increased mucosal dimethylarginine dimethylaminohydrolase-1 (DDAH-1) gene expression and decreased elevated levels of matrix metalloproteinase-9, asymmetric dimethylarginine (ADMA), epidermal growth factor receptor (EGFR) mRNA and phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2). Histopathological evaluation corroborated biochemical findings. Overall efficacy of irbesartan was comparable to ranitidine, the widely used H
2
receptor blocker. In conclusion, irbesartan exerts significant gastroprotection against indomethacin-induced mucosal damage via acid-inhibitory, anti-inflammatory, anti-apoptotic and extracellular matrix remodeling mechanisms that are probably mediated, at least partly, by down-regulating DDAH/ADMA and EGFR/ERK1/2 signaling.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-018-22727-6</identifier><identifier>PMID: 29523851</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/51 ; 14/63 ; 38/77 ; 692/308/2778 ; 692/4020/1503/583/1722 ; Acidity ; Angiotensin ; Angiotensin II ; Apoptosis ; Caspase ; Caspase-3 ; Cyclooxygenase-2 ; Epidermal growth factor ; Epidermal growth factor receptors ; Extracellular matrix ; Extracellular signal-regulated kinase ; Gastric juice ; Gene expression ; Humanities and Social Sciences ; Indomethacin ; Inflammation ; Kinases ; Matrix metalloproteinase ; Metalloproteinase ; Mucosa ; multidisciplinary ; Oral administration ; Pharmacodynamics ; Pharmacokinetics ; Prostaglandin E2 ; Ranitidine ; Rodents ; Science ; Science (multidisciplinary) ; Tumor necrosis factor-α</subject><ispartof>Scientific reports, 2018-03, Vol.8 (1), p.4280-12, Article 4280</ispartof><rights>The Author(s) 2018</rights><rights>2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-9b9945829adc40fef3485325d7896746d71aa13d0af057c2d6e597ead7efbc823</citedby><cites>FETCH-LOGICAL-c474t-9b9945829adc40fef3485325d7896746d71aa13d0af057c2d6e597ead7efbc823</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/PMC5844881/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844881/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27903,27904,41099,42168,51554,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29523851$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shahin, Nancy N.</creatorcontrib><creatorcontrib>Abdelkader, Noha F.</creatorcontrib><creatorcontrib>Safar, Marwa M.</creatorcontrib><title>A Novel Role of Irbesartan in Gastroprotection against Indomethacin-Induced Gastric Injury in Rats: Targeting DDAH/ADMA and EGFR/ERK Signaling</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>The advent of angiotensin II type 1 receptor blockers (ARBs) as intriguing gastroprotective candidates and the superior pharmacokinetics and pharmacodynamics displayed by irbesartan compared to many other ARBs raised the interest to investigate its gastroprotective potential in a rat model of gastric injury. Irbesartan (50 mg/Kg) was orally administered to male Wistar rats once daily for 14 days; thereafter gastric injury was induced by indomethacin (60 mg/Kg, p.o). Irbesartan reduced gastric ulcer index, gastric acidity, and ameliorated indomethacin-induced gastric mucosal apoptotic and inflammatory aberrations, as demonstrated by hampering caspase-3, prostaglandin E
2
and tumor necrosis factor-alpha levels and cyclooxygenase-2 mRNA expression. This ARB increased mucosal dimethylarginine dimethylaminohydrolase-1 (DDAH-1) gene expression and decreased elevated levels of matrix metalloproteinase-9, asymmetric dimethylarginine (ADMA), epidermal growth factor receptor (EGFR) mRNA and phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2). Histopathological evaluation corroborated biochemical findings. Overall efficacy of irbesartan was comparable to ranitidine, the widely used H
2
receptor blocker. In conclusion, irbesartan exerts significant gastroprotection against indomethacin-induced mucosal damage via acid-inhibitory, anti-inflammatory, anti-apoptotic and extracellular matrix remodeling mechanisms that are probably mediated, at least partly, by down-regulating DDAH/ADMA and EGFR/ERK1/2 signaling.</description><subject>13/51</subject><subject>14/63</subject><subject>38/77</subject><subject>692/308/2778</subject><subject>692/4020/1503/583/1722</subject><subject>Acidity</subject><subject>Angiotensin</subject><subject>Angiotensin II</subject><subject>Apoptosis</subject><subject>Caspase</subject><subject>Caspase-3</subject><subject>Cyclooxygenase-2</subject><subject>Epidermal growth factor</subject><subject>Epidermal growth factor receptors</subject><subject>Extracellular matrix</subject><subject>Extracellular signal-regulated kinase</subject><subject>Gastric juice</subject><subject>Gene expression</subject><subject>Humanities and Social Sciences</subject><subject>Indomethacin</subject><subject>Inflammation</subject><subject>Kinases</subject><subject>Matrix metalloproteinase</subject><subject>Metalloproteinase</subject><subject>Mucosa</subject><subject>multidisciplinary</subject><subject>Oral administration</subject><subject>Pharmacodynamics</subject><subject>Pharmacokinetics</subject><subject>Prostaglandin E2</subject><subject>Ranitidine</subject><subject>Rodents</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Tumor necrosis factor-α</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kUFvFCEcxSfGxjZtv4AHQ-LFy7jAwAx4MJl0t9uNVZO1ngkLzJTNLGyBadIv4WeWdWqtHuQC5P3eg39eUbxG8D2CFZtFgihnJUSsxLjBTVm_KE4wJLTEFcYvn52Pi_MYtzAvijlB_FVxjDnFFaPopPjRgi_-3gxg7QcDfAdWYWOiDEk6YB1YypiC3wefjErWOyB7aV1MYOW035l0K5V1Zb6MyuiJtiqL2zE8HPxrmeIHcCNDb5J1PZjP26tZO__cAuk0WCwv17PF-hP4ZnsnhwycFUedHKI5f9xPi--Xi5uLq_L663J10V6XijQklXzDOaEMc6kVgZ3pKsJohaluGK8bUusGSYkqDWUHaaOwrg3ljZG6Md1GMVydFh-n3P242RmtjEtBDmIf7E6GB-GlFX8rzt6K3t8LyghhDOWAd48Bwd-NJiaxs1GZYZDO-DEKDBHmqMaQZvTtP-jWjyHPO1GUwZrWmcITpYKPMZju6TMIikPjYmpc5MbFr8bFwfTm-RhPlt_9ZqCagJgl15vw5-3_xP4EzAC2lg</recordid><startdate>20180309</startdate><enddate>20180309</enddate><creator>Shahin, Nancy N.</creator><creator>Abdelkader, Noha F.</creator><creator>Safar, Marwa M.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180309</creationdate><title>A Novel Role of Irbesartan in Gastroprotection against Indomethacin-Induced Gastric Injury in Rats: Targeting DDAH/ADMA and EGFR/ERK Signaling</title><author>Shahin, Nancy N. ; Abdelkader, Noha F. ; Safar, Marwa M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-9b9945829adc40fef3485325d7896746d71aa13d0af057c2d6e597ead7efbc823</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>13/51</topic><topic>14/63</topic><topic>38/77</topic><topic>692/308/2778</topic><topic>692/4020/1503/583/1722</topic><topic>Acidity</topic><topic>Angiotensin</topic><topic>Angiotensin II</topic><topic>Apoptosis</topic><topic>Caspase</topic><topic>Caspase-3</topic><topic>Cyclooxygenase-2</topic><topic>Epidermal growth factor</topic><topic>Epidermal growth factor receptors</topic><topic>Extracellular matrix</topic><topic>Extracellular signal-regulated kinase</topic><topic>Gastric juice</topic><topic>Gene expression</topic><topic>Humanities and Social Sciences</topic><topic>Indomethacin</topic><topic>Inflammation</topic><topic>Kinases</topic><topic>Matrix metalloproteinase</topic><topic>Metalloproteinase</topic><topic>Mucosa</topic><topic>multidisciplinary</topic><topic>Oral administration</topic><topic>Pharmacodynamics</topic><topic>Pharmacokinetics</topic><topic>Prostaglandin E2</topic><topic>Ranitidine</topic><topic>Rodents</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Tumor necrosis factor-α</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shahin, Nancy N.</creatorcontrib><creatorcontrib>Abdelkader, Noha F.</creatorcontrib><creatorcontrib>Safar, Marwa M.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</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>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</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>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science 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 Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shahin, Nancy N.</au><au>Abdelkader, Noha F.</au><au>Safar, Marwa M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Novel Role of Irbesartan in Gastroprotection against Indomethacin-Induced Gastric Injury in Rats: Targeting DDAH/ADMA and EGFR/ERK Signaling</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2018-03-09</date><risdate>2018</risdate><volume>8</volume><issue>1</issue><spage>4280</spage><epage>12</epage><pages>4280-12</pages><artnum>4280</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>The advent of angiotensin II type 1 receptor blockers (ARBs) as intriguing gastroprotective candidates and the superior pharmacokinetics and pharmacodynamics displayed by irbesartan compared to many other ARBs raised the interest to investigate its gastroprotective potential in a rat model of gastric injury. Irbesartan (50 mg/Kg) was orally administered to male Wistar rats once daily for 14 days; thereafter gastric injury was induced by indomethacin (60 mg/Kg, p.o). Irbesartan reduced gastric ulcer index, gastric acidity, and ameliorated indomethacin-induced gastric mucosal apoptotic and inflammatory aberrations, as demonstrated by hampering caspase-3, prostaglandin E
2
and tumor necrosis factor-alpha levels and cyclooxygenase-2 mRNA expression. This ARB increased mucosal dimethylarginine dimethylaminohydrolase-1 (DDAH-1) gene expression and decreased elevated levels of matrix metalloproteinase-9, asymmetric dimethylarginine (ADMA), epidermal growth factor receptor (EGFR) mRNA and phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2). Histopathological evaluation corroborated biochemical findings. Overall efficacy of irbesartan was comparable to ranitidine, the widely used H
2
receptor blocker. In conclusion, irbesartan exerts significant gastroprotection against indomethacin-induced mucosal damage via acid-inhibitory, anti-inflammatory, anti-apoptotic and extracellular matrix remodeling mechanisms that are probably mediated, at least partly, by down-regulating DDAH/ADMA and EGFR/ERK1/2 signaling.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29523851</pmid><doi>10.1038/s41598-018-22727-6</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13/51 14/63 38/77 692/308/2778 692/4020/1503/583/1722 Acidity Angiotensin Angiotensin II Apoptosis Caspase Caspase-3 Cyclooxygenase-2 Epidermal growth factor Epidermal growth factor receptors Extracellular matrix Extracellular signal-regulated kinase Gastric juice Gene expression Humanities and Social Sciences Indomethacin Inflammation Kinases Matrix metalloproteinase Metalloproteinase Mucosa multidisciplinary Oral administration Pharmacodynamics Pharmacokinetics Prostaglandin E2 Ranitidine Rodents Science Science (multidisciplinary) Tumor necrosis factor-α |
| title | A Novel Role of Irbesartan in Gastroprotection against Indomethacin-Induced Gastric Injury in Rats: Targeting DDAH/ADMA and EGFR/ERK Signaling |
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