A Novel Danshensu-Tetramethylpyrazine Conjugate DT-010 Provides Cardioprotection through the PGC-1α/Nrf2/HO-1 Pathway
In this study, we investigated the cardioprotective mechanisms of action of DT-010, a novel danshensu-tetramethylpyrazine conjugate. DT-010 significantly preserved cell viability and suppressed cell apoptosis in H9c2 cells injured by tert-butylhydroperoxide (t-BHP), iodoacetic acid (IAA) and hypoxia...
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| Veröffentlicht in: | Biological & pharmaceutical bulletin 2017/09/01, Vol.40(9), pp.1490-1498 |
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| creator | Zhang, Xiaojing Hu, Huihui Luo, Jingxiong Deng, Huixing Yu, Pei Zhang, Zaijun Zhang, Gaoxiao Shan, Luchen Wang, Yuqiang |
| description | In this study, we investigated the cardioprotective mechanisms of action of DT-010, a novel danshensu-tetramethylpyrazine conjugate. DT-010 significantly preserved cell viability and suppressed cell apoptosis in H9c2 cells injured by tert-butylhydroperoxide (t-BHP), iodoacetic acid (IAA) and hypoxia-reoxygenation. In addition, DT-010 pre-treatment reduced the intracellular level of free radicals including superoxide anion (·O2−), hydroxyl radical (·OH) and peroxynitrite anion (ONOO−) after t-BHP exposure. Moreover, DT-010 up-regulated the protein expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and nuclear factor-E2-related factor 2 (Nrf2) as well as mitochondrial transcription factor A (Tfam) and heme oxygenase-1 (HO-1) in H9c2 cells. DT-010 also triggered Nrf2 nuclear translocation. In a rat myocardial ischemia-reperfusion model, DT-010 significantly alleviated myocardial infarction. The results indicated that DT-010 may be a promising candidate for the treatment of cardiovascular diseases, particularly myocardial ischemia and reperfusion injury. |
| doi_str_mv | 10.1248/bpb.b17-00313 |
| format | Article |
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DT-010 significantly preserved cell viability and suppressed cell apoptosis in H9c2 cells injured by tert-butylhydroperoxide (t-BHP), iodoacetic acid (IAA) and hypoxia-reoxygenation. In addition, DT-010 pre-treatment reduced the intracellular level of free radicals including superoxide anion (·O2−), hydroxyl radical (·OH) and peroxynitrite anion (ONOO−) after t-BHP exposure. Moreover, DT-010 up-regulated the protein expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and nuclear factor-E2-related factor 2 (Nrf2) as well as mitochondrial transcription factor A (Tfam) and heme oxygenase-1 (HO-1) in H9c2 cells. DT-010 also triggered Nrf2 nuclear translocation. In a rat myocardial ischemia-reperfusion model, DT-010 significantly alleviated myocardial infarction. The results indicated that DT-010 may be a promising candidate for the treatment of cardiovascular diseases, particularly myocardial ischemia and reperfusion injury.</description><identifier>ISSN: 0918-6158</identifier><identifier>EISSN: 1347-5215</identifier><identifier>DOI: 10.1248/bpb.b17-00313</identifier><identifier>PMID: 28637941</identifier><language>eng</language><publisher>Japan: The Pharmaceutical Society of Japan</publisher><subject>Animals ; Apoptosis ; Cardiovascular diseases ; Cell Line ; Cell Survival ; Danshensu derivative ; Free radicals ; Free Radicals - metabolism ; Heme ; Heme oxygenase (decyclizing) ; Heme Oxygenase-1 - metabolism ; Hydroxyl radicals ; Hypoxia ; Iodoacetic Acid ; Ischemia ; Lactates - pharmacology ; Lactates - therapeutic use ; Ligusticum ; Male ; Mitochondria ; Myocardial infarction ; Myocardial Infarction - etiology ; Myocardial Infarction - metabolism ; Myocardial Infarction - prevention & control ; Myocardial ischemia ; Myocardial Ischemia - complications ; Myocardial Ischemia - drug therapy ; Myocardial Ischemia - metabolism ; Myocardial Ischemia - pathology ; myocardial ischemia reperfusion injury ; Myocardium - cytology ; Myocardium - metabolism ; Myocardium - pathology ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - pathology ; NF-E2-Related Factor 2 - metabolism ; Nuclear transport ; Oxidation ; oxidative stress ; Oxygenase ; peroxisome proliferator-activated receptor gamma coactivator 1 alpha/nuclear factor-E2-related factor 2/heme oxygenase-1 (PGC-1α/Nrf2/HO-1) pathway ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism ; Peroxynitrite ; Phytotherapy ; Plant Extracts - pharmacology ; Plant Extracts - therapeutic use ; Pyrazines - pharmacology ; Pyrazines - therapeutic use ; Rats ; Rats, Sprague-Dawley ; Reperfusion ; Reperfusion Injury - drug therapy ; Reperfusion Injury - metabolism ; Reperfusion Injury - pathology ; Rodents ; Salvia miltiorrhiza ; Superoxide ; tert-Butylhydroperoxide ; Translocation ; Up-Regulation</subject><ispartof>Biological and Pharmaceutical Bulletin, 2017/09/01, Vol.40(9), pp.1490-1498</ispartof><rights>2017 The Pharmaceutical Society of Japan</rights><rights>Copyright Japan Science and Technology Agency 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c510t-e4679b4a6c96fd5294680ac915731fa50a28bfb02cfb53f72f4d5b252997f9fa3</citedby><cites>FETCH-LOGICAL-c510t-e4679b4a6c96fd5294680ac915731fa50a28bfb02cfb53f72f4d5b252997f9fa3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,1877,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28637941$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Xiaojing</creatorcontrib><creatorcontrib>Hu, Huihui</creatorcontrib><creatorcontrib>Luo, Jingxiong</creatorcontrib><creatorcontrib>Deng, Huixing</creatorcontrib><creatorcontrib>Yu, Pei</creatorcontrib><creatorcontrib>Zhang, Zaijun</creatorcontrib><creatorcontrib>Zhang, Gaoxiao</creatorcontrib><creatorcontrib>Shan, Luchen</creatorcontrib><creatorcontrib>Wang, Yuqiang</creatorcontrib><title>A Novel Danshensu-Tetramethylpyrazine Conjugate DT-010 Provides Cardioprotection through the PGC-1α/Nrf2/HO-1 Pathway</title><title>Biological & pharmaceutical bulletin</title><addtitle>Biol Pharm Bull</addtitle><description>In this study, we investigated the cardioprotective mechanisms of action of DT-010, a novel danshensu-tetramethylpyrazine conjugate. DT-010 significantly preserved cell viability and suppressed cell apoptosis in H9c2 cells injured by tert-butylhydroperoxide (t-BHP), iodoacetic acid (IAA) and hypoxia-reoxygenation. In addition, DT-010 pre-treatment reduced the intracellular level of free radicals including superoxide anion (·O2−), hydroxyl radical (·OH) and peroxynitrite anion (ONOO−) after t-BHP exposure. Moreover, DT-010 up-regulated the protein expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and nuclear factor-E2-related factor 2 (Nrf2) as well as mitochondrial transcription factor A (Tfam) and heme oxygenase-1 (HO-1) in H9c2 cells. DT-010 also triggered Nrf2 nuclear translocation. In a rat myocardial ischemia-reperfusion model, DT-010 significantly alleviated myocardial infarction. The results indicated that DT-010 may be a promising candidate for the treatment of cardiovascular diseases, particularly myocardial ischemia and reperfusion injury.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Cardiovascular diseases</subject><subject>Cell Line</subject><subject>Cell Survival</subject><subject>Danshensu derivative</subject><subject>Free radicals</subject><subject>Free Radicals - metabolism</subject><subject>Heme</subject><subject>Heme oxygenase (decyclizing)</subject><subject>Heme Oxygenase-1 - metabolism</subject><subject>Hydroxyl radicals</subject><subject>Hypoxia</subject><subject>Iodoacetic Acid</subject><subject>Ischemia</subject><subject>Lactates - pharmacology</subject><subject>Lactates - therapeutic use</subject><subject>Ligusticum</subject><subject>Male</subject><subject>Mitochondria</subject><subject>Myocardial infarction</subject><subject>Myocardial Infarction - etiology</subject><subject>Myocardial Infarction - metabolism</subject><subject>Myocardial Infarction - prevention & control</subject><subject>Myocardial ischemia</subject><subject>Myocardial Ischemia - complications</subject><subject>Myocardial Ischemia - drug therapy</subject><subject>Myocardial Ischemia - metabolism</subject><subject>Myocardial Ischemia - pathology</subject><subject>myocardial ischemia reperfusion injury</subject><subject>Myocardium - cytology</subject><subject>Myocardium - metabolism</subject><subject>Myocardium - pathology</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Myocytes, Cardiac - pathology</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Nuclear transport</subject><subject>Oxidation</subject><subject>oxidative stress</subject><subject>Oxygenase</subject><subject>peroxisome proliferator-activated receptor gamma coactivator 1 alpha/nuclear factor-E2-related factor 2/heme oxygenase-1 (PGC-1α/Nrf2/HO-1) pathway</subject><subject>Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism</subject><subject>Peroxynitrite</subject><subject>Phytotherapy</subject><subject>Plant Extracts - pharmacology</subject><subject>Plant Extracts - therapeutic use</subject><subject>Pyrazines - pharmacology</subject><subject>Pyrazines - therapeutic use</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Reperfusion</subject><subject>Reperfusion Injury - drug therapy</subject><subject>Reperfusion Injury - metabolism</subject><subject>Reperfusion Injury - pathology</subject><subject>Rodents</subject><subject>Salvia miltiorrhiza</subject><subject>Superoxide</subject><subject>tert-Butylhydroperoxide</subject><subject>Translocation</subject><subject>Up-Regulation</subject><issn>0918-6158</issn><issn>1347-5215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpd0b9u2zAQBnCiaNC4SceuhYAuXRjzjyiKY6A0SYEg8eDMBCUdLRmy6JKUA_et-iJ5pjJx6iHL3XA_fDjgQ-grJReU5eW83tYXNZWYEE75BzSjPJdYMCo-ohlRtMQFFeUp-hzCmhAiCeOf0CkrCy5VTmdod5ndux0M2ZUZQwdjmPASojcbiN1-2O69-dOPkFVuXE8rEyG7WmJCSbbwbte3ELLK-LZ3W-8iNLF3YxY776ZVlzZki5sK0-e_83tv2fz2AdNsYWL3ZPbn6MSaIcCXt32GHq9_LqtbfPdw86u6vMONoCRiyAup6twUjSpsK5jKi5KYRlEhObVGEMPK2taENbYW3Epm81bULEElrbKGn6Efh9z04O8JQtSbPjQwDGYENwVNFWUFUYzIRL-_o2s3-TF9lxQXheSloknhg2q8C8GD1Vvfb4zfa0r0SyE6FaJTIfq1kOS_vaVO9Qbao_7fQALVAaxDNCs4AuNj3wzwGpcTrV7GMfZ4bTrjNYz8Hyolng0</recordid><startdate>20170901</startdate><enddate>20170901</enddate><creator>Zhang, Xiaojing</creator><creator>Hu, Huihui</creator><creator>Luo, Jingxiong</creator><creator>Deng, Huixing</creator><creator>Yu, Pei</creator><creator>Zhang, Zaijun</creator><creator>Zhang, Gaoxiao</creator><creator>Shan, Luchen</creator><creator>Wang, Yuqiang</creator><general>The Pharmaceutical Society of Japan</general><general>Japan Science and Technology Agency</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>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20170901</creationdate><title>A Novel Danshensu-Tetramethylpyrazine Conjugate DT-010 Provides Cardioprotection through the PGC-1α/Nrf2/HO-1 Pathway</title><author>Zhang, Xiaojing ; Hu, Huihui ; Luo, Jingxiong ; Deng, Huixing ; Yu, Pei ; Zhang, Zaijun ; Zhang, Gaoxiao ; Shan, Luchen ; Wang, Yuqiang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c510t-e4679b4a6c96fd5294680ac915731fa50a28bfb02cfb53f72f4d5b252997f9fa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Cardiovascular diseases</topic><topic>Cell Line</topic><topic>Cell Survival</topic><topic>Danshensu derivative</topic><topic>Free radicals</topic><topic>Free Radicals - metabolism</topic><topic>Heme</topic><topic>Heme oxygenase (decyclizing)</topic><topic>Heme Oxygenase-1 - metabolism</topic><topic>Hydroxyl radicals</topic><topic>Hypoxia</topic><topic>Iodoacetic Acid</topic><topic>Ischemia</topic><topic>Lactates - pharmacology</topic><topic>Lactates - therapeutic use</topic><topic>Ligusticum</topic><topic>Male</topic><topic>Mitochondria</topic><topic>Myocardial infarction</topic><topic>Myocardial Infarction - etiology</topic><topic>Myocardial Infarction - metabolism</topic><topic>Myocardial Infarction - prevention & control</topic><topic>Myocardial ischemia</topic><topic>Myocardial Ischemia - complications</topic><topic>Myocardial Ischemia - drug therapy</topic><topic>Myocardial Ischemia - metabolism</topic><topic>Myocardial Ischemia - pathology</topic><topic>myocardial ischemia reperfusion injury</topic><topic>Myocardium - cytology</topic><topic>Myocardium - metabolism</topic><topic>Myocardium - pathology</topic><topic>Myocytes, Cardiac - drug effects</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Myocytes, Cardiac - pathology</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>Nuclear transport</topic><topic>Oxidation</topic><topic>oxidative stress</topic><topic>Oxygenase</topic><topic>peroxisome proliferator-activated receptor gamma coactivator 1 alpha/nuclear factor-E2-related factor 2/heme oxygenase-1 (PGC-1α/Nrf2/HO-1) pathway</topic><topic>Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism</topic><topic>Peroxynitrite</topic><topic>Phytotherapy</topic><topic>Plant Extracts - pharmacology</topic><topic>Plant Extracts - therapeutic use</topic><topic>Pyrazines - pharmacology</topic><topic>Pyrazines - therapeutic use</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Reperfusion</topic><topic>Reperfusion Injury - drug therapy</topic><topic>Reperfusion Injury - metabolism</topic><topic>Reperfusion Injury - pathology</topic><topic>Rodents</topic><topic>Salvia miltiorrhiza</topic><topic>Superoxide</topic><topic>tert-Butylhydroperoxide</topic><topic>Translocation</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Xiaojing</creatorcontrib><creatorcontrib>Hu, Huihui</creatorcontrib><creatorcontrib>Luo, Jingxiong</creatorcontrib><creatorcontrib>Deng, Huixing</creatorcontrib><creatorcontrib>Yu, Pei</creatorcontrib><creatorcontrib>Zhang, Zaijun</creatorcontrib><creatorcontrib>Zhang, Gaoxiao</creatorcontrib><creatorcontrib>Shan, Luchen</creatorcontrib><creatorcontrib>Wang, Yuqiang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Biological & pharmaceutical bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Xiaojing</au><au>Hu, Huihui</au><au>Luo, Jingxiong</au><au>Deng, Huixing</au><au>Yu, Pei</au><au>Zhang, Zaijun</au><au>Zhang, Gaoxiao</au><au>Shan, Luchen</au><au>Wang, Yuqiang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Novel Danshensu-Tetramethylpyrazine Conjugate DT-010 Provides Cardioprotection through the PGC-1α/Nrf2/HO-1 Pathway</atitle><jtitle>Biological & pharmaceutical bulletin</jtitle><addtitle>Biol Pharm Bull</addtitle><date>2017-09-01</date><risdate>2017</risdate><volume>40</volume><issue>9</issue><spage>1490</spage><epage>1498</epage><pages>1490-1498</pages><issn>0918-6158</issn><eissn>1347-5215</eissn><abstract>In this study, we investigated the cardioprotective mechanisms of action of DT-010, a novel danshensu-tetramethylpyrazine conjugate. DT-010 significantly preserved cell viability and suppressed cell apoptosis in H9c2 cells injured by tert-butylhydroperoxide (t-BHP), iodoacetic acid (IAA) and hypoxia-reoxygenation. In addition, DT-010 pre-treatment reduced the intracellular level of free radicals including superoxide anion (·O2−), hydroxyl radical (·OH) and peroxynitrite anion (ONOO−) after t-BHP exposure. Moreover, DT-010 up-regulated the protein expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and nuclear factor-E2-related factor 2 (Nrf2) as well as mitochondrial transcription factor A (Tfam) and heme oxygenase-1 (HO-1) in H9c2 cells. DT-010 also triggered Nrf2 nuclear translocation. In a rat myocardial ischemia-reperfusion model, DT-010 significantly alleviated myocardial infarction. The results indicated that DT-010 may be a promising candidate for the treatment of cardiovascular diseases, particularly myocardial ischemia and reperfusion injury.</abstract><cop>Japan</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>28637941</pmid><doi>10.1248/bpb.b17-00313</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis Cardiovascular diseases Cell Line Cell Survival Danshensu derivative Free radicals Free Radicals - metabolism Heme Heme oxygenase (decyclizing) Heme Oxygenase-1 - metabolism Hydroxyl radicals Hypoxia Iodoacetic Acid Ischemia Lactates - pharmacology Lactates - therapeutic use Ligusticum Male Mitochondria Myocardial infarction Myocardial Infarction - etiology Myocardial Infarction - metabolism Myocardial Infarction - prevention & control Myocardial ischemia Myocardial Ischemia - complications Myocardial Ischemia - drug therapy Myocardial Ischemia - metabolism Myocardial Ischemia - pathology myocardial ischemia reperfusion injury Myocardium - cytology Myocardium - metabolism Myocardium - pathology Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology NF-E2-Related Factor 2 - metabolism Nuclear transport Oxidation oxidative stress Oxygenase peroxisome proliferator-activated receptor gamma coactivator 1 alpha/nuclear factor-E2-related factor 2/heme oxygenase-1 (PGC-1α/Nrf2/HO-1) pathway Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism Peroxynitrite Phytotherapy Plant Extracts - pharmacology Plant Extracts - therapeutic use Pyrazines - pharmacology Pyrazines - therapeutic use Rats Rats, Sprague-Dawley Reperfusion Reperfusion Injury - drug therapy Reperfusion Injury - metabolism Reperfusion Injury - pathology Rodents Salvia miltiorrhiza Superoxide tert-Butylhydroperoxide Translocation Up-Regulation |
| title | A Novel Danshensu-Tetramethylpyrazine Conjugate DT-010 Provides Cardioprotection through the PGC-1α/Nrf2/HO-1 Pathway |
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