Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA
Previously, we reported that cAMP/PKA signaling is involved in GPER-mediated coronary relaxation by activating MLCP via inhibition of RhoA pathway. In the current study, we tested the hypothesis that activation of GPER induces coronary artery relaxation via inhibition of RhoA/Rho kinase pathway by c...
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| Veröffentlicht in: | PloS one 2017-03, Vol.12 (3), p.e0173085-e0173085 |
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| creator | Yu, Xuan Zhang, Qiao Zhao, Yan Schwarz, Benjamin J Stallone, John N Heaps, Cristine L Han, Guichun |
| description | Previously, we reported that cAMP/PKA signaling is involved in GPER-mediated coronary relaxation by activating MLCP via inhibition of RhoA pathway. In the current study, we tested the hypothesis that activation of GPER induces coronary artery relaxation via inhibition of RhoA/Rho kinase pathway by cAMP downstream targets, exchange proteins directly activated by cAMP (Epac) as well as PKA. Our results show that Epac inhibitors, brefeldin A (BFA, 50 μM), or ESI-09 (20 μM), or CE3F4 (100 μM), all partially inhibited porcine coronary artery relaxation response to the selective GPER agonist, G-1 (0.3-3 μM); while concurrent administration of BFA and PKI (5 μM), a PKA inhibitor, almost completely blocked the relaxation effect of G-1. The Epac specific agonist, 8-CPT-2Me-cAMP (007, 1-100 μM), induced a concentration-dependent relaxation response. Furthermore, the activity of Ras-related protein 1 (Rap1) was up regulated by G-1 (1 μM) treatment of porcine coronary artery smooth muscle cells (CASMCs). Phosphorylation of vasodilator-stimulated phosphoprotein (p-VASP) was elevated by G-1 (1 μM) treatment, but not by 007 (50 μM); and the effect of G-1 on p-VASP was blocked by PKI, but not by ESI-09, an Epac antagonist. RhoA activity was similarly down regulated by G-1 and 007, whereas ESI-09 restored most of the reduced RhoA activity by G-1 treatment. Furthermore, G-1 decreased PGF2α-induced p-MYPT1, which was partially reversed with either ESI-09 or PKI; whereas, concurrent administration of ESI-09 and PKI totally prevented the inhibitory effect of G-1. The inhibitory effects of G-1 on p- MLC levels in CASMCs were mostly restored by either ESI-09 or PKI. These results demonstrate that activation of GPER induces coronary artery relaxation via concurrent inhibition of RhoA/Rho kinase by Epac/Rap1 and PKA. GPER could be a potential drug target for preventing and treating cardiovascular diseases. |
| doi_str_mv | 10.1371/journal.pone.0173085 |
| format | Article |
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In the current study, we tested the hypothesis that activation of GPER induces coronary artery relaxation via inhibition of RhoA/Rho kinase pathway by cAMP downstream targets, exchange proteins directly activated by cAMP (Epac) as well as PKA. Our results show that Epac inhibitors, brefeldin A (BFA, 50 μM), or ESI-09 (20 μM), or CE3F4 (100 μM), all partially inhibited porcine coronary artery relaxation response to the selective GPER agonist, G-1 (0.3-3 μM); while concurrent administration of BFA and PKI (5 μM), a PKA inhibitor, almost completely blocked the relaxation effect of G-1. The Epac specific agonist, 8-CPT-2Me-cAMP (007, 1-100 μM), induced a concentration-dependent relaxation response. Furthermore, the activity of Ras-related protein 1 (Rap1) was up regulated by G-1 (1 μM) treatment of porcine coronary artery smooth muscle cells (CASMCs). Phosphorylation of vasodilator-stimulated phosphoprotein (p-VASP) was elevated by G-1 (1 μM) treatment, but not by 007 (50 μM); and the effect of G-1 on p-VASP was blocked by PKI, but not by ESI-09, an Epac antagonist. RhoA activity was similarly down regulated by G-1 and 007, whereas ESI-09 restored most of the reduced RhoA activity by G-1 treatment. Furthermore, G-1 decreased PGF2α-induced p-MYPT1, which was partially reversed with either ESI-09 or PKI; whereas, concurrent administration of ESI-09 and PKI totally prevented the inhibitory effect of G-1. The inhibitory effects of G-1 on p- MLC levels in CASMCs were mostly restored by either ESI-09 or PKI. These results demonstrate that activation of GPER induces coronary artery relaxation via concurrent inhibition of RhoA/Rho kinase by Epac/Rap1 and PKA. GPER could be a potential drug target for preventing and treating cardiovascular diseases.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0173085</identifier><identifier>PMID: 28278256</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Animals ; Biology and Life Sciences ; Blood pressure ; Brefeldin A ; Cardiovascular diseases ; Cells, Cultured ; Coronary artery ; Coronary vessels ; Coronary Vessels - physiology ; Cyclic adenosine monophosphate ; Cyclic AMP ; Cyclic AMP - analogs & derivatives ; Cyclic AMP - pharmacology ; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors ; Cyclic AMP-Dependent Protein Kinases - metabolism ; Cyclopentanes - pharmacology ; Endothelium ; Estrogen receptors ; Estrogens ; G proteins ; Guanine Nucleotide Exchange Factors - antagonists & inhibitors ; Guanine Nucleotide Exchange Factors - metabolism ; Heart diseases ; Hydrazones - pharmacology ; Inhibition ; Isoxazoles - pharmacology ; Kinases ; Medicine and Health Sciences ; Muscle contraction ; Muscle, Smooth, Vascular - cytology ; Muscle, Smooth, Vascular - drug effects ; Muscle, Smooth, Vascular - metabolism ; Muscles ; Myosin-Light-Chain Phosphatase - metabolism ; Myosin-light-chain-phosphatase ; Pharmacology ; Phosphatase ; Phosphorylation ; Phosphorylation - drug effects ; Physiology ; Protein kinase A ; Proteins ; Quinolines - pharmacology ; rap1 GTP-Binding Proteins - antagonists & inhibitors ; rap1 GTP-Binding Proteins - genetics ; rap1 GTP-Binding Proteins - metabolism ; Rap1 protein ; Receptors, Estrogen - metabolism ; Research and Analysis Methods ; Rho-associated kinase ; rho-Associated Kinases - metabolism ; rhoA GTP-Binding Protein - metabolism ; RhoA protein ; RNA Interference ; RNA, Small Interfering - metabolism ; Signal Transduction - drug effects ; Signaling ; Smooth muscle ; Swine ; Thionucleotides - pharmacology ; Vasodilator-stimulated phosphoprotein ; Veins & arteries ; Womens health</subject><ispartof>PloS one, 2017-03, Vol.12 (3), p.e0173085-e0173085</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Yu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Yu et al 2017 Yu et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c725t-b99d43afe6002676c28f31660b44b49b1cb5984d66d762c08a891f41ab6e5ad23</citedby><cites>FETCH-LOGICAL-c725t-b99d43afe6002676c28f31660b44b49b1cb5984d66d762c08a891f41ab6e5ad23</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/PMC5344336/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344336/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28278256$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Chrzanowska-Wodnicka, Magdalena</contributor><creatorcontrib>Yu, Xuan</creatorcontrib><creatorcontrib>Zhang, Qiao</creatorcontrib><creatorcontrib>Zhao, Yan</creatorcontrib><creatorcontrib>Schwarz, Benjamin J</creatorcontrib><creatorcontrib>Stallone, John N</creatorcontrib><creatorcontrib>Heaps, Cristine L</creatorcontrib><creatorcontrib>Han, Guichun</creatorcontrib><title>Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Previously, we reported that cAMP/PKA signaling is involved in GPER-mediated coronary relaxation by activating MLCP via inhibition of RhoA pathway. In the current study, we tested the hypothesis that activation of GPER induces coronary artery relaxation via inhibition of RhoA/Rho kinase pathway by cAMP downstream targets, exchange proteins directly activated by cAMP (Epac) as well as PKA. Our results show that Epac inhibitors, brefeldin A (BFA, 50 μM), or ESI-09 (20 μM), or CE3F4 (100 μM), all partially inhibited porcine coronary artery relaxation response to the selective GPER agonist, G-1 (0.3-3 μM); while concurrent administration of BFA and PKI (5 μM), a PKA inhibitor, almost completely blocked the relaxation effect of G-1. The Epac specific agonist, 8-CPT-2Me-cAMP (007, 1-100 μM), induced a concentration-dependent relaxation response. Furthermore, the activity of Ras-related protein 1 (Rap1) was up regulated by G-1 (1 μM) treatment of porcine coronary artery smooth muscle cells (CASMCs). Phosphorylation of vasodilator-stimulated phosphoprotein (p-VASP) was elevated by G-1 (1 μM) treatment, but not by 007 (50 μM); and the effect of G-1 on p-VASP was blocked by PKI, but not by ESI-09, an Epac antagonist. RhoA activity was similarly down regulated by G-1 and 007, whereas ESI-09 restored most of the reduced RhoA activity by G-1 treatment. Furthermore, G-1 decreased PGF2α-induced p-MYPT1, which was partially reversed with either ESI-09 or PKI; whereas, concurrent administration of ESI-09 and PKI totally prevented the inhibitory effect of G-1. The inhibitory effects of G-1 on p- MLC levels in CASMCs were mostly restored by either ESI-09 or PKI. These results demonstrate that activation of GPER induces coronary artery relaxation via concurrent inhibition of RhoA/Rho kinase by Epac/Rap1 and PKA. GPER could be a potential drug target for preventing and treating cardiovascular diseases.</description><subject>Activation</subject><subject>Animals</subject><subject>Biology and Life Sciences</subject><subject>Blood pressure</subject><subject>Brefeldin A</subject><subject>Cardiovascular diseases</subject><subject>Cells, Cultured</subject><subject>Coronary artery</subject><subject>Coronary vessels</subject><subject>Coronary Vessels - physiology</subject><subject>Cyclic adenosine monophosphate</subject><subject>Cyclic AMP</subject><subject>Cyclic AMP - analogs & derivatives</subject><subject>Cyclic AMP - pharmacology</subject><subject>Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors</subject><subject>Cyclic AMP-Dependent Protein Kinases - metabolism</subject><subject>Cyclopentanes - pharmacology</subject><subject>Endothelium</subject><subject>Estrogen receptors</subject><subject>Estrogens</subject><subject>G proteins</subject><subject>Guanine Nucleotide Exchange Factors - antagonists & inhibitors</subject><subject>Guanine Nucleotide Exchange Factors - metabolism</subject><subject>Heart diseases</subject><subject>Hydrazones - pharmacology</subject><subject>Inhibition</subject><subject>Isoxazoles - pharmacology</subject><subject>Kinases</subject><subject>Medicine and Health Sciences</subject><subject>Muscle contraction</subject><subject>Muscle, Smooth, Vascular - cytology</subject><subject>Muscle, Smooth, Vascular - drug effects</subject><subject>Muscle, Smooth, Vascular - metabolism</subject><subject>Muscles</subject><subject>Myosin-Light-Chain Phosphatase - metabolism</subject><subject>Myosin-light-chain-phosphatase</subject><subject>Pharmacology</subject><subject>Phosphatase</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Physiology</subject><subject>Protein kinase A</subject><subject>Proteins</subject><subject>Quinolines - pharmacology</subject><subject>rap1 GTP-Binding Proteins - antagonists & inhibitors</subject><subject>rap1 GTP-Binding Proteins - genetics</subject><subject>rap1 GTP-Binding Proteins - metabolism</subject><subject>Rap1 protein</subject><subject>Receptors, Estrogen - metabolism</subject><subject>Research and Analysis Methods</subject><subject>Rho-associated kinase</subject><subject>rho-Associated Kinases - metabolism</subject><subject>rhoA GTP-Binding Protein - metabolism</subject><subject>RhoA protein</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Signaling</subject><subject>Smooth muscle</subject><subject>Swine</subject><subject>Thionucleotides - pharmacology</subject><subject>Vasodilator-stimulated phosphoprotein</subject><subject>Veins & arteries</subject><subject>Womens health</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk11rFDEUhgdRbK3-A9GAIHqx23xNJnMjLKXWxUKlftyGTCazk5pNxiTTj3_kzzTb3ZZd6UUZSELmOe85eZNTFK8RnCJSocMLPwYn7XTwTk8hqgjk5ZNiH9UETxiG5OnWeq94EeMFhCXhjD0v9jDHFccl2y_-zlQylzIZ74DvwAkYgk_auIny42B1C3RMwS-0A0ErPSQfAALGtaPSESgfvJPhBsiQdJ6CtvJ6rXVpJDgepDo8lwOaLHVrZMpqxvWmMXfZzns_O8wD-G2cjBoMMvVX8iZTeRmktdqCK5N68O3r7GXxrJM26leb-aD4-fn4x9GXyenZyfxodjpRFS7TpKnrlhLZaQYhZhVTmHcEMQYbShtaN0g1Zc1py1hbMawgl7xGHUWyYbqULSYHxdu17mB9FBuTo0C8Knm2DaNMzNdE6-WFGIJZZguEl0bcbviwENkPo6wWCFUla3FNOgYphZQz1TUKq5I1LZRNmbU-bbKNTTZJaZfyuXdEd_8404uFvxQloZQQlgU-bASC_zPmyxJLE5W2Vjrtx1XdPNdQsfoxaMVKCGku96B49x_6sBEbaiHzWY3rfC5RrUTFjHJaUQhv004foPLX6qVR-fF2Ju_vBHzcCchM0tdpIccYxfz7-ePZs1-77PstttfSpj56O65eY9wF6RpUwccYdHd_HwiKVe_duSFWvSc2vZfD3mzf5X3QXbORf3lEKk8</recordid><startdate>20170309</startdate><enddate>20170309</enddate><creator>Yu, Xuan</creator><creator>Zhang, Qiao</creator><creator>Zhao, Yan</creator><creator>Schwarz, Benjamin J</creator><creator>Stallone, John N</creator><creator>Heaps, Cristine L</creator><creator>Han, Guichun</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20170309</creationdate><title>Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA</title><author>Yu, Xuan ; Zhang, Qiao ; Zhao, Yan ; Schwarz, Benjamin J ; Stallone, John N ; Heaps, Cristine L ; Han, Guichun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c725t-b99d43afe6002676c28f31660b44b49b1cb5984d66d762c08a891f41ab6e5ad23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Activation</topic><topic>Animals</topic><topic>Biology and Life Sciences</topic><topic>Blood pressure</topic><topic>Brefeldin A</topic><topic>Cardiovascular diseases</topic><topic>Cells, Cultured</topic><topic>Coronary artery</topic><topic>Coronary vessels</topic><topic>Coronary Vessels - physiology</topic><topic>Cyclic adenosine monophosphate</topic><topic>Cyclic AMP</topic><topic>Cyclic AMP - analogs & derivatives</topic><topic>Cyclic AMP - pharmacology</topic><topic>Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors</topic><topic>Cyclic AMP-Dependent Protein Kinases - metabolism</topic><topic>Cyclopentanes - pharmacology</topic><topic>Endothelium</topic><topic>Estrogen receptors</topic><topic>Estrogens</topic><topic>G proteins</topic><topic>Guanine Nucleotide Exchange Factors - antagonists & inhibitors</topic><topic>Guanine Nucleotide Exchange Factors - metabolism</topic><topic>Heart diseases</topic><topic>Hydrazones - pharmacology</topic><topic>Inhibition</topic><topic>Isoxazoles - pharmacology</topic><topic>Kinases</topic><topic>Medicine and Health Sciences</topic><topic>Muscle contraction</topic><topic>Muscle, Smooth, Vascular - cytology</topic><topic>Muscle, Smooth, Vascular - drug effects</topic><topic>Muscle, Smooth, Vascular - metabolism</topic><topic>Muscles</topic><topic>Myosin-Light-Chain Phosphatase - metabolism</topic><topic>Myosin-light-chain-phosphatase</topic><topic>Pharmacology</topic><topic>Phosphatase</topic><topic>Phosphorylation</topic><topic>Phosphorylation - drug effects</topic><topic>Physiology</topic><topic>Protein kinase A</topic><topic>Proteins</topic><topic>Quinolines - pharmacology</topic><topic>rap1 GTP-Binding Proteins - antagonists & inhibitors</topic><topic>rap1 GTP-Binding Proteins - genetics</topic><topic>rap1 GTP-Binding Proteins - metabolism</topic><topic>Rap1 protein</topic><topic>Receptors, Estrogen - metabolism</topic><topic>Research and Analysis Methods</topic><topic>Rho-associated kinase</topic><topic>rho-Associated Kinases - metabolism</topic><topic>rhoA GTP-Binding Protein - metabolism</topic><topic>RhoA protein</topic><topic>RNA Interference</topic><topic>RNA, Small Interfering - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Signaling</topic><topic>Smooth muscle</topic><topic>Swine</topic><topic>Thionucleotides - pharmacology</topic><topic>Vasodilator-stimulated phosphoprotein</topic><topic>Veins & arteries</topic><topic>Womens health</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yu, Xuan</creatorcontrib><creatorcontrib>Zhang, Qiao</creatorcontrib><creatorcontrib>Zhao, Yan</creatorcontrib><creatorcontrib>Schwarz, Benjamin J</creatorcontrib><creatorcontrib>Stallone, John N</creatorcontrib><creatorcontrib>Heaps, Cristine L</creatorcontrib><creatorcontrib>Han, Guichun</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 In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology 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>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yu, Xuan</au><au>Zhang, Qiao</au><au>Zhao, Yan</au><au>Schwarz, Benjamin J</au><au>Stallone, John N</au><au>Heaps, Cristine L</au><au>Han, Guichun</au><au>Chrzanowska-Wodnicka, Magdalena</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-03-09</date><risdate>2017</risdate><volume>12</volume><issue>3</issue><spage>e0173085</spage><epage>e0173085</epage><pages>e0173085-e0173085</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Previously, we reported that cAMP/PKA signaling is involved in GPER-mediated coronary relaxation by activating MLCP via inhibition of RhoA pathway. In the current study, we tested the hypothesis that activation of GPER induces coronary artery relaxation via inhibition of RhoA/Rho kinase pathway by cAMP downstream targets, exchange proteins directly activated by cAMP (Epac) as well as PKA. Our results show that Epac inhibitors, brefeldin A (BFA, 50 μM), or ESI-09 (20 μM), or CE3F4 (100 μM), all partially inhibited porcine coronary artery relaxation response to the selective GPER agonist, G-1 (0.3-3 μM); while concurrent administration of BFA and PKI (5 μM), a PKA inhibitor, almost completely blocked the relaxation effect of G-1. The Epac specific agonist, 8-CPT-2Me-cAMP (007, 1-100 μM), induced a concentration-dependent relaxation response. Furthermore, the activity of Ras-related protein 1 (Rap1) was up regulated by G-1 (1 μM) treatment of porcine coronary artery smooth muscle cells (CASMCs). Phosphorylation of vasodilator-stimulated phosphoprotein (p-VASP) was elevated by G-1 (1 μM) treatment, but not by 007 (50 μM); and the effect of G-1 on p-VASP was blocked by PKI, but not by ESI-09, an Epac antagonist. RhoA activity was similarly down regulated by G-1 and 007, whereas ESI-09 restored most of the reduced RhoA activity by G-1 treatment. Furthermore, G-1 decreased PGF2α-induced p-MYPT1, which was partially reversed with either ESI-09 or PKI; whereas, concurrent administration of ESI-09 and PKI totally prevented the inhibitory effect of G-1. The inhibitory effects of G-1 on p- MLC levels in CASMCs were mostly restored by either ESI-09 or PKI. These results demonstrate that activation of GPER induces coronary artery relaxation via concurrent inhibition of RhoA/Rho kinase by Epac/Rap1 and PKA. GPER could be a potential drug target for preventing and treating cardiovascular diseases.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28278256</pmid><doi>10.1371/journal.pone.0173085</doi><tpages>e0173085</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2017-03, Vol.12 (3), p.e0173085-e0173085 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1875828221 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Activation Animals Biology and Life Sciences Blood pressure Brefeldin A Cardiovascular diseases Cells, Cultured Coronary artery Coronary vessels Coronary Vessels - physiology Cyclic adenosine monophosphate Cyclic AMP Cyclic AMP - analogs & derivatives Cyclic AMP - pharmacology Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors Cyclic AMP-Dependent Protein Kinases - metabolism Cyclopentanes - pharmacology Endothelium Estrogen receptors Estrogens G proteins Guanine Nucleotide Exchange Factors - antagonists & inhibitors Guanine Nucleotide Exchange Factors - metabolism Heart diseases Hydrazones - pharmacology Inhibition Isoxazoles - pharmacology Kinases Medicine and Health Sciences Muscle contraction Muscle, Smooth, Vascular - cytology Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - metabolism Muscles Myosin-Light-Chain Phosphatase - metabolism Myosin-light-chain-phosphatase Pharmacology Phosphatase Phosphorylation Phosphorylation - drug effects Physiology Protein kinase A Proteins Quinolines - pharmacology rap1 GTP-Binding Proteins - antagonists & inhibitors rap1 GTP-Binding Proteins - genetics rap1 GTP-Binding Proteins - metabolism Rap1 protein Receptors, Estrogen - metabolism Research and Analysis Methods Rho-associated kinase rho-Associated Kinases - metabolism rhoA GTP-Binding Protein - metabolism RhoA protein RNA Interference RNA, Small Interfering - metabolism Signal Transduction - drug effects Signaling Smooth muscle Swine Thionucleotides - pharmacology Vasodilator-stimulated phosphoprotein Veins & arteries Womens health |
| title | Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA |
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