Pravastatin Effects on Placental Prosurvival Molecular Pathways in a Mouse Model of Preeclampsia
Objective: Using an animal model of preeclampsia induced by overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1), we previously showed that pravastatin prevents the development of a preeclampsia phenotype. Our objective is to determine whether pravastatin treatment may be explained by its e...
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| Veröffentlicht in: | Reproductive sciences (Thousand Oaks, Calif.) Calif.), 2016-11, Vol.23 (11), p.1593-1599 |
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| creator | Saad, Antonio F. Diken, Zaid M. Kechichian, Talar B. Clark, Shannon M. Olson, Gayle L. Saade, George R. Costantine, Maged M. |
| description | Objective:
Using an animal model of preeclampsia induced by overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1), we previously showed that pravastatin prevents the development of a preeclampsia phenotype. Our objective is to determine whether pravastatin treatment may be explained by its effects on apoptotic/survival pathways in the placenta.
Methods:
Pregnant CD1 mice at day 8 of gestation (length of gestation 19 days) were randomly allocated to injection via tail vein with either adenovirus carrying sFlt-1 or adenovirus carrying the murine immunoglobulin G2α Fc fragment (mFc virus control group). Mice from the sFlt group were randomly assigned to receive pravastatin (5 mg/kg/d) in their drinking water from day 9 until killing (sFlt-1 + Pravastatin) or water (sFlt-1). The mFc control received water only. Mice were killed on day 18, and the placentas were collected. Protein mitogen-activated protein kinase (MAPK) pathway substrates were assayed using Bioplex Multiplex Immunoassay (Bio-Rad, Hercules, California). Data are reported as mean ± standard error of the mean or median (interquartile range) when appropriate. One-way analysis of variance followed by post hoc analysis was performed. Two-sided P value |
| doi_str_mv | 10.1177/1933719116648218 |
| format | Article |
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Using an animal model of preeclampsia induced by overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1), we previously showed that pravastatin prevents the development of a preeclampsia phenotype. Our objective is to determine whether pravastatin treatment may be explained by its effects on apoptotic/survival pathways in the placenta.
Methods:
Pregnant CD1 mice at day 8 of gestation (length of gestation 19 days) were randomly allocated to injection via tail vein with either adenovirus carrying sFlt-1 or adenovirus carrying the murine immunoglobulin G2α Fc fragment (mFc virus control group). Mice from the sFlt group were randomly assigned to receive pravastatin (5 mg/kg/d) in their drinking water from day 9 until killing (sFlt-1 + Pravastatin) or water (sFlt-1). The mFc control received water only. Mice were killed on day 18, and the placentas were collected. Protein mitogen-activated protein kinase (MAPK) pathway substrates were assayed using Bioplex Multiplex Immunoassay (Bio-Rad, Hercules, California). Data are reported as mean ± standard error of the mean or median (interquartile range) when appropriate. One-way analysis of variance followed by post hoc analysis was performed. Two-sided P value < .05 was considered statistically significant.
Results:
The sFlt-1 + Pravastatin mice had significantly higher placental protein concentrations of prosurvival/ antiapoptotic factors (activating transcription factor 2, pp38, phosphorylated c-jun N-terminal kinase, and phosphorylated extracellular signal-regulated kinase) and of heat-shock protein 27 and signal transducer and activator of transcription 3, 2 factors crucial for embryonic and placental development during oxidative stress, compared to sFlt-1 mice (P < .05) and similar to the mFc control group. No differences were noted in substrates of the proapoptotic pp53 pathway.
Conclusion:
Pravastatin ability to prevent preeclampsia phenotype may be mediated through pleiotropic mechanisms involving a prosurvival/ antiapoptotic MAPK pathway in the placenta. Our results further support continued research in the role for statins in the prevention of preeclampsia.</description><identifier>ISSN: 1933-7191</identifier><identifier>EISSN: 1933-7205</identifier><identifier>DOI: 10.1177/1933719116648218</identifier><identifier>PMID: 27170663</identifier><language>eng</language><publisher>Los Angeles, CA: SAGE Publications</publisher><subject>Animals ; Apoptosis - drug effects ; Disease Models, Animal ; Embryology ; Female ; HSP27 Heat-Shock Proteins - metabolism ; MAP Kinase Signaling System - drug effects ; Medicine & Public Health ; Mice ; Obstetrics/Perinatology/Midwifery ; Original Article ; Phosphorylation ; Placenta - drug effects ; Placenta - metabolism ; Pravastatin - administration & dosage ; Pre-Eclampsia - metabolism ; Pre-Eclampsia - prevention & control ; Pregnancy ; Reproductive Medicine ; STAT3 Transcription Factor - metabolism ; Vascular Endothelial Growth Factor Receptor-1 - metabolism</subject><ispartof>Reproductive sciences (Thousand Oaks, Calif.), 2016-11, Vol.23 (11), p.1593-1599</ispartof><rights>The Author(s) 2016</rights><rights>The Author(s) 2016.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c379t-2644d56e5310a1f469c3d0b732db30016cfa9285cfcea93a3ba227b2f12a2c6d3</citedby><cites>FETCH-LOGICAL-c379t-2644d56e5310a1f469c3d0b732db30016cfa9285cfcea93a3ba227b2f12a2c6d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://journals.sagepub.com/doi/pdf/10.1177/1933719116648218$$EPDF$$P50$$Gsage$$H</linktopdf><linktohtml>$$Uhttps://journals.sagepub.com/doi/10.1177/1933719116648218$$EHTML$$P50$$Gsage$$H</linktohtml><link.rule.ids>314,778,782,21808,27913,27914,41477,42546,43610,43611,51308</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27170663$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Saad, Antonio F.</creatorcontrib><creatorcontrib>Diken, Zaid M.</creatorcontrib><creatorcontrib>Kechichian, Talar B.</creatorcontrib><creatorcontrib>Clark, Shannon M.</creatorcontrib><creatorcontrib>Olson, Gayle L.</creatorcontrib><creatorcontrib>Saade, George R.</creatorcontrib><creatorcontrib>Costantine, Maged M.</creatorcontrib><title>Pravastatin Effects on Placental Prosurvival Molecular Pathways in a Mouse Model of Preeclampsia</title><title>Reproductive sciences (Thousand Oaks, Calif.)</title><addtitle>Reprod. Sci</addtitle><addtitle>Reprod Sci</addtitle><description>Objective:
Using an animal model of preeclampsia induced by overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1), we previously showed that pravastatin prevents the development of a preeclampsia phenotype. Our objective is to determine whether pravastatin treatment may be explained by its effects on apoptotic/survival pathways in the placenta.
Methods:
Pregnant CD1 mice at day 8 of gestation (length of gestation 19 days) were randomly allocated to injection via tail vein with either adenovirus carrying sFlt-1 or adenovirus carrying the murine immunoglobulin G2α Fc fragment (mFc virus control group). Mice from the sFlt group were randomly assigned to receive pravastatin (5 mg/kg/d) in their drinking water from day 9 until killing (sFlt-1 + Pravastatin) or water (sFlt-1). The mFc control received water only. Mice were killed on day 18, and the placentas were collected. Protein mitogen-activated protein kinase (MAPK) pathway substrates were assayed using Bioplex Multiplex Immunoassay (Bio-Rad, Hercules, California). Data are reported as mean ± standard error of the mean or median (interquartile range) when appropriate. One-way analysis of variance followed by post hoc analysis was performed. Two-sided P value < .05 was considered statistically significant.
Results:
The sFlt-1 + Pravastatin mice had significantly higher placental protein concentrations of prosurvival/ antiapoptotic factors (activating transcription factor 2, pp38, phosphorylated c-jun N-terminal kinase, and phosphorylated extracellular signal-regulated kinase) and of heat-shock protein 27 and signal transducer and activator of transcription 3, 2 factors crucial for embryonic and placental development during oxidative stress, compared to sFlt-1 mice (P < .05) and similar to the mFc control group. No differences were noted in substrates of the proapoptotic pp53 pathway.
Conclusion:
Pravastatin ability to prevent preeclampsia phenotype may be mediated through pleiotropic mechanisms involving a prosurvival/ antiapoptotic MAPK pathway in the placenta. Our results further support continued research in the role for statins in the prevention of preeclampsia.</description><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>Disease Models, Animal</subject><subject>Embryology</subject><subject>Female</subject><subject>HSP27 Heat-Shock Proteins - metabolism</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Obstetrics/Perinatology/Midwifery</subject><subject>Original Article</subject><subject>Phosphorylation</subject><subject>Placenta - drug effects</subject><subject>Placenta - metabolism</subject><subject>Pravastatin - administration & dosage</subject><subject>Pre-Eclampsia - metabolism</subject><subject>Pre-Eclampsia - prevention & control</subject><subject>Pregnancy</subject><subject>Reproductive Medicine</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Vascular Endothelial Growth Factor Receptor-1 - metabolism</subject><issn>1933-7191</issn><issn>1933-7205</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkL1PwzAQxS0EoqWwM6GMLAF_JHYyoqp8SEV0gDlcnHNJ5SbFTor63-OqLQMDYrFPd-_3dPcIuWT0hjGlblkuhGI5Y1ImGWfZERluW7HiND0-1GE-IGfeLyhNk5xnp2TAFVNUSjEk7zMHa_AddHUTTYxB3fmobaKZBY1NBzaaudb3bl2vQ_3cWtS9BRfNoPv4go2PAgah33sMb4U2ak1AELWF5crXcE5ODFiPF_t_RN7uJ6_jx3j68vA0vpvGWqi8i7lMkiqVmApGgZlE5lpUtFSCV6WglEltIOyeaqMRcgGiBM5VyQ3jwLWsxIhc73xXrv3s0XfFsvYarYUGw3YFy7iUKssyGaR0J9XhNO_QFCtXL8FtCkaLba7F71wDcrV378slVj_AIcggYDuBD6Nmjq5YtL1rwsV_mcZ7Bub4D_03KXiO2g</recordid><startdate>20161101</startdate><enddate>20161101</enddate><creator>Saad, Antonio F.</creator><creator>Diken, Zaid M.</creator><creator>Kechichian, Talar B.</creator><creator>Clark, Shannon M.</creator><creator>Olson, Gayle L.</creator><creator>Saade, George R.</creator><creator>Costantine, Maged M.</creator><general>SAGE Publications</general><general>Springer International Publishing</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>7X8</scope></search><sort><creationdate>20161101</creationdate><title>Pravastatin Effects on Placental Prosurvival Molecular Pathways in a Mouse Model of Preeclampsia</title><author>Saad, Antonio F. ; Diken, Zaid M. ; Kechichian, Talar B. ; Clark, Shannon M. ; Olson, Gayle L. ; Saade, George R. ; Costantine, Maged M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c379t-2644d56e5310a1f469c3d0b732db30016cfa9285cfcea93a3ba227b2f12a2c6d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Apoptosis - drug effects</topic><topic>Disease Models, Animal</topic><topic>Embryology</topic><topic>Female</topic><topic>HSP27 Heat-Shock Proteins - metabolism</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Obstetrics/Perinatology/Midwifery</topic><topic>Original Article</topic><topic>Phosphorylation</topic><topic>Placenta - drug effects</topic><topic>Placenta - metabolism</topic><topic>Pravastatin - administration & dosage</topic><topic>Pre-Eclampsia - metabolism</topic><topic>Pre-Eclampsia - prevention & control</topic><topic>Pregnancy</topic><topic>Reproductive Medicine</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Vascular Endothelial Growth Factor Receptor-1 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Saad, Antonio F.</creatorcontrib><creatorcontrib>Diken, Zaid M.</creatorcontrib><creatorcontrib>Kechichian, Talar B.</creatorcontrib><creatorcontrib>Clark, Shannon M.</creatorcontrib><creatorcontrib>Olson, Gayle L.</creatorcontrib><creatorcontrib>Saade, George R.</creatorcontrib><creatorcontrib>Costantine, Maged M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Reproductive sciences (Thousand Oaks, Calif.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Saad, Antonio F.</au><au>Diken, Zaid M.</au><au>Kechichian, Talar B.</au><au>Clark, Shannon M.</au><au>Olson, Gayle L.</au><au>Saade, George R.</au><au>Costantine, Maged M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pravastatin Effects on Placental Prosurvival Molecular Pathways in a Mouse Model of Preeclampsia</atitle><jtitle>Reproductive sciences (Thousand Oaks, Calif.)</jtitle><stitle>Reprod. Sci</stitle><addtitle>Reprod Sci</addtitle><date>2016-11-01</date><risdate>2016</risdate><volume>23</volume><issue>11</issue><spage>1593</spage><epage>1599</epage><pages>1593-1599</pages><issn>1933-7191</issn><eissn>1933-7205</eissn><abstract>Objective:
Using an animal model of preeclampsia induced by overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1), we previously showed that pravastatin prevents the development of a preeclampsia phenotype. Our objective is to determine whether pravastatin treatment may be explained by its effects on apoptotic/survival pathways in the placenta.
Methods:
Pregnant CD1 mice at day 8 of gestation (length of gestation 19 days) were randomly allocated to injection via tail vein with either adenovirus carrying sFlt-1 or adenovirus carrying the murine immunoglobulin G2α Fc fragment (mFc virus control group). Mice from the sFlt group were randomly assigned to receive pravastatin (5 mg/kg/d) in their drinking water from day 9 until killing (sFlt-1 + Pravastatin) or water (sFlt-1). The mFc control received water only. Mice were killed on day 18, and the placentas were collected. Protein mitogen-activated protein kinase (MAPK) pathway substrates were assayed using Bioplex Multiplex Immunoassay (Bio-Rad, Hercules, California). Data are reported as mean ± standard error of the mean or median (interquartile range) when appropriate. One-way analysis of variance followed by post hoc analysis was performed. Two-sided P value < .05 was considered statistically significant.
Results:
The sFlt-1 + Pravastatin mice had significantly higher placental protein concentrations of prosurvival/ antiapoptotic factors (activating transcription factor 2, pp38, phosphorylated c-jun N-terminal kinase, and phosphorylated extracellular signal-regulated kinase) and of heat-shock protein 27 and signal transducer and activator of transcription 3, 2 factors crucial for embryonic and placental development during oxidative stress, compared to sFlt-1 mice (P < .05) and similar to the mFc control group. No differences were noted in substrates of the proapoptotic pp53 pathway.
Conclusion:
Pravastatin ability to prevent preeclampsia phenotype may be mediated through pleiotropic mechanisms involving a prosurvival/ antiapoptotic MAPK pathway in the placenta. Our results further support continued research in the role for statins in the prevention of preeclampsia.</abstract><cop>Los Angeles, CA</cop><pub>SAGE Publications</pub><pmid>27170663</pmid><doi>10.1177/1933719116648218</doi><tpages>7</tpages></addata></record> |
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| source | MEDLINE; SAGE Complete A-Z List; Springer Nature - Complete Springer Journals; Alma/SFX Local Collection |
| subjects | Animals Apoptosis - drug effects Disease Models, Animal Embryology Female HSP27 Heat-Shock Proteins - metabolism MAP Kinase Signaling System - drug effects Medicine & Public Health Mice Obstetrics/Perinatology/Midwifery Original Article Phosphorylation Placenta - drug effects Placenta - metabolism Pravastatin - administration & dosage Pre-Eclampsia - metabolism Pre-Eclampsia - prevention & control Pregnancy Reproductive Medicine STAT3 Transcription Factor - metabolism Vascular Endothelial Growth Factor Receptor-1 - metabolism |
| title | Pravastatin Effects on Placental Prosurvival Molecular Pathways in a Mouse Model of Preeclampsia |
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