Mechanisms of sex differences in TNFR2-mediated cardioprotection
TNFR1/TNFR2 signaling may mediate different cellular and molecular responses (injury versus protection) and the balance may be affected by sex hormones. Previous studies have shown that females have improved myocardial functional recovery, TNFR1 signaling resistance, and increased SOCS3 expression a...
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| Veröffentlicht in: | Circulation (New York, N.Y.) N.Y.), 2008-09, Vol.118 (14 Suppl), p.S38-S45 |
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| creator | Wang, Meijing Crisostomo, Paul R Markel, Troy A Wang, Yue Meldrum, Daniel R |
| description | TNFR1/TNFR2 signaling may mediate different cellular and molecular responses (injury versus protection) and the balance may be affected by sex hormones. Previous studies have shown that females have improved myocardial functional recovery, TNFR1 signaling resistance, and increased SOCS3 expression after acute ischemia/reperfusion when compared with males. However, it is unknown whether the TNFR2 pathway protects the myocardium from ischemia/reperfusion injury, and if so, whether sex differences exist in TNFR2-mediated cardioprotection. Therefore, we hypothesized that (1) TNFR2 mediates myocardial protection from ischemia/reperfusion through STAT3, SOCS3, and vascular endothelial growth factor in both sexes; and (2) TNFR2 elicits greater protective signaling in females compared with males.
Isolated male and female mouse hearts from TNFR2 knockout, TNFR1/2 knockout, and wild-type (C57BL/6J or B6129SF2/J; n=5 to 6/group) were subjected to 20 minutes ischemia followed by 60 minutes reperfusion. TNFR2 deficiency decreased postischemic myocardial recovery in both sexes but had a greater effect on females. The deleterious effects of TNFR2 ablation were associated with a decrease in mRNA and protein levels of SOCS3, STAT3, and vascular endothelial growth factor as well as an increase in myocardial interleukin-1-beta production in female hearts. However, a significant increase in JNK activation and interleukin-1-beta protein levels was noted in male TNFR2KO hearts after ischemia/reperfusion. Additionally, TNFR1/2 knockout decreased myocardial function in female hearts but not males. This observation was associated with a decrease in mRNA levels of SOCS3, STAT3, and vascular endothelial growth factor and an increase in myocardial p38 mitogen-activated protein kinase activation in females.
Sex differences in the mechanisms of TNFR2-mediated cardioprotection occur by increasing STAT3, SOCS3, and vascular endothelial growth factor in females and by decreasing JNK in males. |
| doi_str_mv | 10.1161/circulationaha.107.756890 |
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Isolated male and female mouse hearts from TNFR2 knockout, TNFR1/2 knockout, and wild-type (C57BL/6J or B6129SF2/J; n=5 to 6/group) were subjected to 20 minutes ischemia followed by 60 minutes reperfusion. TNFR2 deficiency decreased postischemic myocardial recovery in both sexes but had a greater effect on females. The deleterious effects of TNFR2 ablation were associated with a decrease in mRNA and protein levels of SOCS3, STAT3, and vascular endothelial growth factor as well as an increase in myocardial interleukin-1-beta production in female hearts. However, a significant increase in JNK activation and interleukin-1-beta protein levels was noted in male TNFR2KO hearts after ischemia/reperfusion. Additionally, TNFR1/2 knockout decreased myocardial function in female hearts but not males. This observation was associated with a decrease in mRNA levels of SOCS3, STAT3, and vascular endothelial growth factor and an increase in myocardial p38 mitogen-activated protein kinase activation in females.
Sex differences in the mechanisms of TNFR2-mediated cardioprotection occur by increasing STAT3, SOCS3, and vascular endothelial growth factor in females and by decreasing JNK in males.</description><identifier>ISSN: 0009-7322</identifier><identifier>EISSN: 1524-4539</identifier><identifier>DOI: 10.1161/circulationaha.107.756890</identifier><identifier>PMID: 18824767</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Apoptosis ; Down-Regulation ; Enzyme Activation ; Female ; Heart - physiopathology ; In Vitro Techniques ; Interleukin-1beta - biosynthesis ; Male ; Mice ; Mice, Knockout ; Mitogen-Activated Protein Kinases - metabolism ; Myocardial Reperfusion Injury - metabolism ; Myocardial Reperfusion Injury - physiopathology ; Myocardial Reperfusion Injury - prevention & control ; Myocardium - metabolism ; Receptors, Tumor Necrosis Factor, Type I - deficiency ; Receptors, Tumor Necrosis Factor, Type I - metabolism ; Receptors, Tumor Necrosis Factor, Type II - deficiency ; Receptors, Tumor Necrosis Factor, Type II - metabolism ; Recovery of Function ; RNA, Messenger - metabolism ; Sex Characteristics ; Signal Transduction ; STAT3 Transcription Factor - genetics ; STAT3 Transcription Factor - metabolism ; Suppressor of Cytokine Signaling Proteins - genetics ; Suppressor of Cytokine Signaling Proteins - metabolism ; Up-Regulation ; Vascular Endothelial Growth Factor A - genetics ; Vascular Endothelial Growth Factor A - metabolism</subject><ispartof>Circulation (New York, N.Y.), 2008-09, Vol.118 (14 Suppl), p.S38-S45</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c537t-67c833af5c76173a4e27674f59a77a8526c4aa33f1d00234c9812832e1717aa33</citedby><cites>FETCH-LOGICAL-c537t-67c833af5c76173a4e27674f59a77a8526c4aa33f1d00234c9812832e1717aa33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3687,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18824767$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Meijing</creatorcontrib><creatorcontrib>Crisostomo, Paul R</creatorcontrib><creatorcontrib>Markel, Troy A</creatorcontrib><creatorcontrib>Wang, Yue</creatorcontrib><creatorcontrib>Meldrum, Daniel R</creatorcontrib><title>Mechanisms of sex differences in TNFR2-mediated cardioprotection</title><title>Circulation (New York, N.Y.)</title><addtitle>Circulation</addtitle><description>TNFR1/TNFR2 signaling may mediate different cellular and molecular responses (injury versus protection) and the balance may be affected by sex hormones. Previous studies have shown that females have improved myocardial functional recovery, TNFR1 signaling resistance, and increased SOCS3 expression after acute ischemia/reperfusion when compared with males. However, it is unknown whether the TNFR2 pathway protects the myocardium from ischemia/reperfusion injury, and if so, whether sex differences exist in TNFR2-mediated cardioprotection. Therefore, we hypothesized that (1) TNFR2 mediates myocardial protection from ischemia/reperfusion through STAT3, SOCS3, and vascular endothelial growth factor in both sexes; and (2) TNFR2 elicits greater protective signaling in females compared with males.
Isolated male and female mouse hearts from TNFR2 knockout, TNFR1/2 knockout, and wild-type (C57BL/6J or B6129SF2/J; n=5 to 6/group) were subjected to 20 minutes ischemia followed by 60 minutes reperfusion. TNFR2 deficiency decreased postischemic myocardial recovery in both sexes but had a greater effect on females. The deleterious effects of TNFR2 ablation were associated with a decrease in mRNA and protein levels of SOCS3, STAT3, and vascular endothelial growth factor as well as an increase in myocardial interleukin-1-beta production in female hearts. However, a significant increase in JNK activation and interleukin-1-beta protein levels was noted in male TNFR2KO hearts after ischemia/reperfusion. Additionally, TNFR1/2 knockout decreased myocardial function in female hearts but not males. This observation was associated with a decrease in mRNA levels of SOCS3, STAT3, and vascular endothelial growth factor and an increase in myocardial p38 mitogen-activated protein kinase activation in females.
Sex differences in the mechanisms of TNFR2-mediated cardioprotection occur by increasing STAT3, SOCS3, and vascular endothelial growth factor in females and by decreasing JNK in males.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Down-Regulation</subject><subject>Enzyme Activation</subject><subject>Female</subject><subject>Heart - physiopathology</subject><subject>In Vitro Techniques</subject><subject>Interleukin-1beta - biosynthesis</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Myocardial Reperfusion Injury - metabolism</subject><subject>Myocardial Reperfusion Injury - physiopathology</subject><subject>Myocardial Reperfusion Injury - prevention & control</subject><subject>Myocardium - metabolism</subject><subject>Receptors, Tumor Necrosis Factor, Type I - deficiency</subject><subject>Receptors, Tumor Necrosis Factor, Type I - metabolism</subject><subject>Receptors, Tumor Necrosis Factor, Type II - deficiency</subject><subject>Receptors, Tumor Necrosis Factor, Type II - metabolism</subject><subject>Recovery of Function</subject><subject>RNA, Messenger - metabolism</subject><subject>Sex Characteristics</subject><subject>Signal Transduction</subject><subject>STAT3 Transcription Factor - genetics</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Suppressor of Cytokine Signaling Proteins - genetics</subject><subject>Suppressor of Cytokine Signaling Proteins - metabolism</subject><subject>Up-Regulation</subject><subject>Vascular Endothelial Growth Factor A - genetics</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><issn>0009-7322</issn><issn>1524-4539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUFtPwjAUboxGEP0LZr74NuxlbbcXIyEiJAgJgefm2HVSs63YDqP_3i0QL08n53znu-RD6IbgISGC3Gnr9b6ExroatjAkWA4lF2mGT1CfcJrECWfZKepjjLNYMkp76CKEt3YVTPJz1CNpShMpZB89PBu9hdqGKkSuiIL5jHJbFMabWpsQ2TpaLyYrGlcmt9CYPNLgc-t23jVGdwEu0VkBZTBXxzlAm8njejyN58un2Xg0jzVnsomF1CljUHAtBZEMEkNb_6TgGUgJKadCJwCMFSTHmLJEZymhKaOGSCI7YIDuD7q7_UsbRpu68VCqnbcV-C_lwKr_SG236tV9KCo4J0y0ArdHAe_e9yY0qrJBm7KE2rh9UCITmDPWOWWHR-1dCN4UPyYEq65_NZ6txpv5aD1bLkbTUXuW6tB_y73-m_KXeSycfQPpV4S5</recordid><startdate>20080930</startdate><enddate>20080930</enddate><creator>Wang, Meijing</creator><creator>Crisostomo, Paul R</creator><creator>Markel, Troy A</creator><creator>Wang, Yue</creator><creator>Meldrum, Daniel R</creator><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>5PM</scope></search><sort><creationdate>20080930</creationdate><title>Mechanisms of sex differences in TNFR2-mediated cardioprotection</title><author>Wang, Meijing ; Crisostomo, Paul R ; Markel, Troy A ; Wang, Yue ; Meldrum, Daniel R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c537t-67c833af5c76173a4e27674f59a77a8526c4aa33f1d00234c9812832e1717aa33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Down-Regulation</topic><topic>Enzyme Activation</topic><topic>Female</topic><topic>Heart - physiopathology</topic><topic>In Vitro Techniques</topic><topic>Interleukin-1beta - biosynthesis</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Myocardial Reperfusion Injury - metabolism</topic><topic>Myocardial Reperfusion Injury - physiopathology</topic><topic>Myocardial Reperfusion Injury - prevention & control</topic><topic>Myocardium - metabolism</topic><topic>Receptors, Tumor Necrosis Factor, Type I - deficiency</topic><topic>Receptors, Tumor Necrosis Factor, Type I - metabolism</topic><topic>Receptors, Tumor Necrosis Factor, Type II - deficiency</topic><topic>Receptors, Tumor Necrosis Factor, Type II - metabolism</topic><topic>Recovery of Function</topic><topic>RNA, Messenger - metabolism</topic><topic>Sex Characteristics</topic><topic>Signal Transduction</topic><topic>STAT3 Transcription Factor - genetics</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Suppressor of Cytokine Signaling Proteins - genetics</topic><topic>Suppressor of Cytokine Signaling Proteins - metabolism</topic><topic>Up-Regulation</topic><topic>Vascular Endothelial Growth Factor A - genetics</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Meijing</creatorcontrib><creatorcontrib>Crisostomo, Paul R</creatorcontrib><creatorcontrib>Markel, Troy A</creatorcontrib><creatorcontrib>Wang, Yue</creatorcontrib><creatorcontrib>Meldrum, Daniel R</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>PubMed Central (Full Participant titles)</collection><jtitle>Circulation (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Meijing</au><au>Crisostomo, Paul R</au><au>Markel, Troy A</au><au>Wang, Yue</au><au>Meldrum, Daniel R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanisms of sex differences in TNFR2-mediated cardioprotection</atitle><jtitle>Circulation (New York, N.Y.)</jtitle><addtitle>Circulation</addtitle><date>2008-09-30</date><risdate>2008</risdate><volume>118</volume><issue>14 Suppl</issue><spage>S38</spage><epage>S45</epage><pages>S38-S45</pages><issn>0009-7322</issn><eissn>1524-4539</eissn><abstract>TNFR1/TNFR2 signaling may mediate different cellular and molecular responses (injury versus protection) and the balance may be affected by sex hormones. Previous studies have shown that females have improved myocardial functional recovery, TNFR1 signaling resistance, and increased SOCS3 expression after acute ischemia/reperfusion when compared with males. However, it is unknown whether the TNFR2 pathway protects the myocardium from ischemia/reperfusion injury, and if so, whether sex differences exist in TNFR2-mediated cardioprotection. Therefore, we hypothesized that (1) TNFR2 mediates myocardial protection from ischemia/reperfusion through STAT3, SOCS3, and vascular endothelial growth factor in both sexes; and (2) TNFR2 elicits greater protective signaling in females compared with males.
Isolated male and female mouse hearts from TNFR2 knockout, TNFR1/2 knockout, and wild-type (C57BL/6J or B6129SF2/J; n=5 to 6/group) were subjected to 20 minutes ischemia followed by 60 minutes reperfusion. TNFR2 deficiency decreased postischemic myocardial recovery in both sexes but had a greater effect on females. The deleterious effects of TNFR2 ablation were associated with a decrease in mRNA and protein levels of SOCS3, STAT3, and vascular endothelial growth factor as well as an increase in myocardial interleukin-1-beta production in female hearts. However, a significant increase in JNK activation and interleukin-1-beta protein levels was noted in male TNFR2KO hearts after ischemia/reperfusion. Additionally, TNFR1/2 knockout decreased myocardial function in female hearts but not males. This observation was associated with a decrease in mRNA levels of SOCS3, STAT3, and vascular endothelial growth factor and an increase in myocardial p38 mitogen-activated protein kinase activation in females.
Sex differences in the mechanisms of TNFR2-mediated cardioprotection occur by increasing STAT3, SOCS3, and vascular endothelial growth factor in females and by decreasing JNK in males.</abstract><cop>United States</cop><pmid>18824767</pmid><doi>10.1161/circulationaha.107.756890</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | Circulation (New York, N.Y.), 2008-09, Vol.118 (14 Suppl), p.S38-S45 |
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| source | MEDLINE; American Heart Association Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Journals@Ovid Ovid Autoload |
| subjects | Animals Apoptosis Down-Regulation Enzyme Activation Female Heart - physiopathology In Vitro Techniques Interleukin-1beta - biosynthesis Male Mice Mice, Knockout Mitogen-Activated Protein Kinases - metabolism Myocardial Reperfusion Injury - metabolism Myocardial Reperfusion Injury - physiopathology Myocardial Reperfusion Injury - prevention & control Myocardium - metabolism Receptors, Tumor Necrosis Factor, Type I - deficiency Receptors, Tumor Necrosis Factor, Type I - metabolism Receptors, Tumor Necrosis Factor, Type II - deficiency Receptors, Tumor Necrosis Factor, Type II - metabolism Recovery of Function RNA, Messenger - metabolism Sex Characteristics Signal Transduction STAT3 Transcription Factor - genetics STAT3 Transcription Factor - metabolism Suppressor of Cytokine Signaling Proteins - genetics Suppressor of Cytokine Signaling Proteins - metabolism Up-Regulation Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor A - metabolism |
| title | Mechanisms of sex differences in TNFR2-mediated cardioprotection |
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