Systematic analysis of rat 12/15‐lipoxygenase enzymes reveals critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia
Previously, we observed significant increases in spinal 12‐lipoxygenase (LOX) metabolites, in particular, hepoxilins, which contribute to peripheral inflammation‐induced tactile allodynia. However, the enzymatic sources of hepoxilin synthase (HXS) activity in rats remain elusive. Therefore, we overe...
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| Veröffentlicht in: | The FASEB journal 2013-05, Vol.27 (5), p.1939-1949 |
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| creator | Gregus, Ann M. Dumlao, Darren S. Wei, Spencer C. Norris, Paul C. Catella, Laura C. Meyerstein, Flore G. Buczynski, Matthew W. Steinauer, Joanne J. Fitzsimmons, Bethany L. Yaksh, Tony L. Dennis, Edward A. |
| description | Previously, we observed significant increases in spinal 12‐lipoxygenase (LOX) metabolites, in particular, hepoxilins, which contribute to peripheral inflammation‐induced tactile allodynia. However, the enzymatic sources of hepoxilin synthase (HXS) activity in rats remain elusive. Therefore, we overexpressed each of the 6 rat 12/15‐LOX enzymes in HEK‐293T cells and measured by LC‐MS/MS the formation of HXB3, 12‐HETE, 8‐HETE, and 15‐HETE from arachidonic acid (AA) at baseline and in the presence of LOX inhibitors (NDGA, AA‐861, CDC, baicalein, and PD146176) vs. vehicle‐treated and mock‐transfected controls. We detected the following primary intrinsic activities: 12‐LOX (Alox12, Alox15), 15‐LOX (Alox15b), and HXS (Alox12, Alox15). Similar to human and mouse orthologs, proteins encoded by rat Alox12b and Alox12e possessed minimal 12‐LOX activity with AA as substrate, while eLOX3 (encoded by Aloxe3) exhibited HXS without 12‐LOX activity when coexpressed with Alox12b or supplemented with 12‐HpETE. CDC potently inhibited HXS and 12‐LOX activity in vitro (relative IC50s: CDC, ~0.5 and 0.8 μM, respectively) and carrageenan‐evoked tactile allodynia in vivo. Notably, peripheral inflammation significantly increased spinal eLOX3; intrathecal pretreatment with either siRNA targeting Aloxe3 or an eLOX3‐selective antibody attenuated the associated allodynia. These findings implicate spinal eLOX3‐mediated hepoxilin synthesis in inflammatory hyperesthesia and underscore the importance of developing more selective 12‐LOX/HXS inhibitors.—Gregus, A. M., Dumlao, D. S., Wei, S. C., Norris, P. C., Catella, L. C., Meyerstein, F. G., Buczynski, M. W., Steinauer, J. J., Fitzsimmons, B. L., Yaksh, T. L., Dennis, E. A. Systematic analysis of rat 12/15‐lipoxygenase enzymes reveals critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia. FASEB J. 27, 1939–1949 (2013). www.fasebj.org |
| doi_str_mv | 10.1096/fj.12-217414 |
| format | Article |
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However, the enzymatic sources of hepoxilin synthase (HXS) activity in rats remain elusive. Therefore, we overexpressed each of the 6 rat 12/15‐LOX enzymes in HEK‐293T cells and measured by LC‐MS/MS the formation of HXB3, 12‐HETE, 8‐HETE, and 15‐HETE from arachidonic acid (AA) at baseline and in the presence of LOX inhibitors (NDGA, AA‐861, CDC, baicalein, and PD146176) vs. vehicle‐treated and mock‐transfected controls. We detected the following primary intrinsic activities: 12‐LOX (Alox12, Alox15), 15‐LOX (Alox15b), and HXS (Alox12, Alox15). Similar to human and mouse orthologs, proteins encoded by rat Alox12b and Alox12e possessed minimal 12‐LOX activity with AA as substrate, while eLOX3 (encoded by Aloxe3) exhibited HXS without 12‐LOX activity when coexpressed with Alox12b or supplemented with 12‐HpETE. CDC potently inhibited HXS and 12‐LOX activity in vitro (relative IC50s: CDC, ~0.5 and 0.8 μM, respectively) and carrageenan‐evoked tactile allodynia in vivo. Notably, peripheral inflammation significantly increased spinal eLOX3; intrathecal pretreatment with either siRNA targeting Aloxe3 or an eLOX3‐selective antibody attenuated the associated allodynia. These findings implicate spinal eLOX3‐mediated hepoxilin synthesis in inflammatory hyperesthesia and underscore the importance of developing more selective 12‐LOX/HXS inhibitors.—Gregus, A. M., Dumlao, D. S., Wei, S. C., Norris, P. C., Catella, L. C., Meyerstein, F. G., Buczynski, M. W., Steinauer, J. J., Fitzsimmons, B. L., Yaksh, T. L., Dennis, E. A. Systematic analysis of rat 12/15‐lipoxygenase enzymes reveals critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia. FASEB J. 27, 1939–1949 (2013). www.fasebj.org</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.12-217414</identifier><identifier>PMID: 23382512</identifier><language>eng</language><publisher>United States: The Federation of American Societies for Experimental Biology</publisher><subject>Aloxe3 ; Animals ; Arachidonate 12-Lipoxygenase - drug effects ; Arachidonate 12-Lipoxygenase - metabolism ; Arachidonate 15-Lipoxygenase - drug effects ; Arachidonate 15-Lipoxygenase - metabolism ; eicosanoid ; HEK293 Cells ; Humans ; Hyperalgesia - etiology ; Intramolecular Oxidoreductases - metabolism ; Lipoxygenase Inhibitors - pharmacology ; Male ; pain ; Rats ; Research Communications</subject><ispartof>The FASEB journal, 2013-05, Vol.27 (5), p.1939-1949</ispartof><rights>FASEB</rights><rights>FASEB 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5315-982d240fc3a2145be73264f8388317675cf7947d459f777b0df82a6d140f56be3</citedby><cites>FETCH-LOGICAL-c5315-982d240fc3a2145be73264f8388317675cf7947d459f777b0df82a6d140f56be3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1096%2Ffj.12-217414$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1096%2Ffj.12-217414$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,777,781,882,1412,27905,27906,45555,45556</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23382512$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gregus, Ann M.</creatorcontrib><creatorcontrib>Dumlao, Darren S.</creatorcontrib><creatorcontrib>Wei, Spencer C.</creatorcontrib><creatorcontrib>Norris, Paul C.</creatorcontrib><creatorcontrib>Catella, Laura C.</creatorcontrib><creatorcontrib>Meyerstein, Flore G.</creatorcontrib><creatorcontrib>Buczynski, Matthew W.</creatorcontrib><creatorcontrib>Steinauer, Joanne J.</creatorcontrib><creatorcontrib>Fitzsimmons, Bethany L.</creatorcontrib><creatorcontrib>Yaksh, Tony L.</creatorcontrib><creatorcontrib>Dennis, Edward A.</creatorcontrib><title>Systematic analysis of rat 12/15‐lipoxygenase enzymes reveals critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>Previously, we observed significant increases in spinal 12‐lipoxygenase (LOX) metabolites, in particular, hepoxilins, which contribute to peripheral inflammation‐induced tactile allodynia. However, the enzymatic sources of hepoxilin synthase (HXS) activity in rats remain elusive. Therefore, we overexpressed each of the 6 rat 12/15‐LOX enzymes in HEK‐293T cells and measured by LC‐MS/MS the formation of HXB3, 12‐HETE, 8‐HETE, and 15‐HETE from arachidonic acid (AA) at baseline and in the presence of LOX inhibitors (NDGA, AA‐861, CDC, baicalein, and PD146176) vs. vehicle‐treated and mock‐transfected controls. We detected the following primary intrinsic activities: 12‐LOX (Alox12, Alox15), 15‐LOX (Alox15b), and HXS (Alox12, Alox15). Similar to human and mouse orthologs, proteins encoded by rat Alox12b and Alox12e possessed minimal 12‐LOX activity with AA as substrate, while eLOX3 (encoded by Aloxe3) exhibited HXS without 12‐LOX activity when coexpressed with Alox12b or supplemented with 12‐HpETE. CDC potently inhibited HXS and 12‐LOX activity in vitro (relative IC50s: CDC, ~0.5 and 0.8 μM, respectively) and carrageenan‐evoked tactile allodynia in vivo. Notably, peripheral inflammation significantly increased spinal eLOX3; intrathecal pretreatment with either siRNA targeting Aloxe3 or an eLOX3‐selective antibody attenuated the associated allodynia. These findings implicate spinal eLOX3‐mediated hepoxilin synthesis in inflammatory hyperesthesia and underscore the importance of developing more selective 12‐LOX/HXS inhibitors.—Gregus, A. M., Dumlao, D. S., Wei, S. C., Norris, P. C., Catella, L. C., Meyerstein, F. G., Buczynski, M. W., Steinauer, J. J., Fitzsimmons, B. L., Yaksh, T. L., Dennis, E. A. Systematic analysis of rat 12/15‐lipoxygenase enzymes reveals critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia. FASEB J. 27, 1939–1949 (2013). www.fasebj.org</description><subject>Aloxe3</subject><subject>Animals</subject><subject>Arachidonate 12-Lipoxygenase - drug effects</subject><subject>Arachidonate 12-Lipoxygenase - metabolism</subject><subject>Arachidonate 15-Lipoxygenase - drug effects</subject><subject>Arachidonate 15-Lipoxygenase - metabolism</subject><subject>eicosanoid</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Hyperalgesia - etiology</subject><subject>Intramolecular Oxidoreductases - metabolism</subject><subject>Lipoxygenase Inhibitors - pharmacology</subject><subject>Male</subject><subject>pain</subject><subject>Rats</subject><subject>Research Communications</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkr1uFDEURkcIRJZAR41cUjCJ_z3TIJGIANJKKQISneWdud71yjMe7NkFp8oj0PF-PAmONkTQQGXJPt_xvb6uqucEnxDcylO7PSG0pkRxwh9UCyIYrmUj8cNqgZuW1lKy5qh6ktIWY0wwkY-rI8pYQwWhi-rHVU4zDGZ2HTKj8Tm5hIJF0cyI0FMift58924K3_IaRpMAwXidB0gowh6MT6iLrmSNRzF4QDZElCZXRAiWl58Z2kDJOu9GlPI4b24Nppvd3s0ZlU03Wm-Gcn2IGW3yBNH4NSRnnlaPbNHDs7v1uPp08fbj-ft6efnuw_mbZd0JRkTdNrSnHNuOGUq4WIFiVHLbsKZhREklOqtarnouWquUWuHeNtTInpSMkCtgx9Xrg3farQboOxjnUoKeohtMzDoYp_8-Gd1Gr8NeM1nekLAieHkniOHLDtKsB5c68N6MEHZJEykxx1i04v8o40o1irdtQV8d0C6GlCLY-4oI1rdj13arCdWHsRf8xZ9d3MO_51wAdQC-Og_5nzJ9cXVGMVWlZlw-0y__fbx_</recordid><startdate>201305</startdate><enddate>201305</enddate><creator>Gregus, Ann M.</creator><creator>Dumlao, Darren S.</creator><creator>Wei, Spencer C.</creator><creator>Norris, Paul C.</creator><creator>Catella, Laura C.</creator><creator>Meyerstein, Flore G.</creator><creator>Buczynski, Matthew W.</creator><creator>Steinauer, Joanne J.</creator><creator>Fitzsimmons, Bethany L.</creator><creator>Yaksh, Tony L.</creator><creator>Dennis, Edward A.</creator><general>The Federation of American Societies for Experimental Biology</general><general>Federation of American Societies for Experimental Biology</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><scope>7TK</scope><scope>5PM</scope></search><sort><creationdate>201305</creationdate><title>Systematic analysis of rat 12/15‐lipoxygenase enzymes reveals critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia</title><author>Gregus, Ann M. ; Dumlao, Darren S. ; Wei, Spencer C. ; Norris, Paul C. ; Catella, Laura C. ; Meyerstein, Flore G. ; Buczynski, Matthew W. ; Steinauer, Joanne J. ; Fitzsimmons, Bethany L. ; Yaksh, Tony L. ; Dennis, Edward A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5315-982d240fc3a2145be73264f8388317675cf7947d459f777b0df82a6d140f56be3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Aloxe3</topic><topic>Animals</topic><topic>Arachidonate 12-Lipoxygenase - drug effects</topic><topic>Arachidonate 12-Lipoxygenase - metabolism</topic><topic>Arachidonate 15-Lipoxygenase - drug effects</topic><topic>Arachidonate 15-Lipoxygenase - metabolism</topic><topic>eicosanoid</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Hyperalgesia - etiology</topic><topic>Intramolecular Oxidoreductases - metabolism</topic><topic>Lipoxygenase Inhibitors - pharmacology</topic><topic>Male</topic><topic>pain</topic><topic>Rats</topic><topic>Research Communications</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gregus, Ann M.</creatorcontrib><creatorcontrib>Dumlao, Darren S.</creatorcontrib><creatorcontrib>Wei, Spencer C.</creatorcontrib><creatorcontrib>Norris, Paul C.</creatorcontrib><creatorcontrib>Catella, Laura C.</creatorcontrib><creatorcontrib>Meyerstein, Flore G.</creatorcontrib><creatorcontrib>Buczynski, Matthew W.</creatorcontrib><creatorcontrib>Steinauer, Joanne J.</creatorcontrib><creatorcontrib>Fitzsimmons, Bethany L.</creatorcontrib><creatorcontrib>Yaksh, Tony L.</creatorcontrib><creatorcontrib>Dennis, Edward A.</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><collection>Neurosciences Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gregus, Ann M.</au><au>Dumlao, Darren S.</au><au>Wei, Spencer C.</au><au>Norris, Paul C.</au><au>Catella, Laura C.</au><au>Meyerstein, Flore G.</au><au>Buczynski, Matthew W.</au><au>Steinauer, Joanne J.</au><au>Fitzsimmons, Bethany L.</au><au>Yaksh, Tony L.</au><au>Dennis, Edward A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Systematic analysis of rat 12/15‐lipoxygenase enzymes reveals critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2013-05</date><risdate>2013</risdate><volume>27</volume><issue>5</issue><spage>1939</spage><epage>1949</epage><pages>1939-1949</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><abstract>Previously, we observed significant increases in spinal 12‐lipoxygenase (LOX) metabolites, in particular, hepoxilins, which contribute to peripheral inflammation‐induced tactile allodynia. However, the enzymatic sources of hepoxilin synthase (HXS) activity in rats remain elusive. Therefore, we overexpressed each of the 6 rat 12/15‐LOX enzymes in HEK‐293T cells and measured by LC‐MS/MS the formation of HXB3, 12‐HETE, 8‐HETE, and 15‐HETE from arachidonic acid (AA) at baseline and in the presence of LOX inhibitors (NDGA, AA‐861, CDC, baicalein, and PD146176) vs. vehicle‐treated and mock‐transfected controls. We detected the following primary intrinsic activities: 12‐LOX (Alox12, Alox15), 15‐LOX (Alox15b), and HXS (Alox12, Alox15). Similar to human and mouse orthologs, proteins encoded by rat Alox12b and Alox12e possessed minimal 12‐LOX activity with AA as substrate, while eLOX3 (encoded by Aloxe3) exhibited HXS without 12‐LOX activity when coexpressed with Alox12b or supplemented with 12‐HpETE. CDC potently inhibited HXS and 12‐LOX activity in vitro (relative IC50s: CDC, ~0.5 and 0.8 μM, respectively) and carrageenan‐evoked tactile allodynia in vivo. Notably, peripheral inflammation significantly increased spinal eLOX3; intrathecal pretreatment with either siRNA targeting Aloxe3 or an eLOX3‐selective antibody attenuated the associated allodynia. These findings implicate spinal eLOX3‐mediated hepoxilin synthesis in inflammatory hyperesthesia and underscore the importance of developing more selective 12‐LOX/HXS inhibitors.—Gregus, A. M., Dumlao, D. S., Wei, S. C., Norris, P. C., Catella, L. C., Meyerstein, F. G., Buczynski, M. W., Steinauer, J. J., Fitzsimmons, B. L., Yaksh, T. L., Dennis, E. A. Systematic analysis of rat 12/15‐lipoxygenase enzymes reveals critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia. FASEB J. 27, 1939–1949 (2013). www.fasebj.org</abstract><cop>United States</cop><pub>The Federation of American Societies for Experimental Biology</pub><pmid>23382512</pmid><doi>10.1096/fj.12-217414</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aloxe3 Animals Arachidonate 12-Lipoxygenase - drug effects Arachidonate 12-Lipoxygenase - metabolism Arachidonate 15-Lipoxygenase - drug effects Arachidonate 15-Lipoxygenase - metabolism eicosanoid HEK293 Cells Humans Hyperalgesia - etiology Intramolecular Oxidoreductases - metabolism Lipoxygenase Inhibitors - pharmacology Male pain Rats Research Communications |
| title | Systematic analysis of rat 12/15‐lipoxygenase enzymes reveals critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia |
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