Arachidonate 12/15-lipoxygenase-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy
Diabetes affects cardiac structure and function, and it has been suggested that diabetes leads to cardiomyopathy. Arachidonate 12/15-lipoxygenase (LOX) has been suggested to play an important role in atherogenesis and heart failure. However, the role of 12/15-LOX in diabetic cardiomyopathy has not b...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2015-02, Vol.64 (2), p.618-630 |
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| creator | Suzuki, Hirofumi Kayama, Yosuke Sakamoto, Masaya Iuchi, Hiroyuki Shimizu, Ippei Yoshino, Takuya Katoh, Daisuke Nagoshi, Tomohisa Tojo, Katsuyoshi Minamino, Tohru Yoshimura, Michihiro Utsunomiya, Kazunori |
| description | Diabetes affects cardiac structure and function, and it has been suggested that diabetes leads to cardiomyopathy. Arachidonate 12/15-lipoxygenase (LOX) has been suggested to play an important role in atherogenesis and heart failure. However, the role of 12/15-LOX in diabetic cardiomyopathy has not been examined. In this study, we investigated the effects of cardiac 12/15-LOX on diabetic cardiomyopathy. We created streptozotocin (STZ)-induced diabetic mice and compared them with Alox15-deficient mice. Expression of 12/15-LOX and inflammatory cytokines such as tumor necrosis factor (TNF)-α and nuclear factor (NF)-κB were upregulated in STZ-induced diabetic hearts. Disruption of 12/15-LOX significantly improved STZ-induced cardiac dysfunction and fibrosis. Moreover, deletion of 12/15-LOX inhibited the increases of TNF-α and NF-κB as well as the production of STZ-induced reactive oxygen species in the heart. Administration of N-acetylcysteine in diabetic mice prevented STZ-induced cardiac fibrosis. Neonatal cultured cardiomyocytes exposed to high glucose conditions induced the expression of 12/15-LOX as well as TNF-α, NF-κB, and collagen markers. These increases were inhibited by treatment of the 12/15-LOX inhibitor. Our results suggest that cardiac 12/15-LOX-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy and that inhibition of 12/15-LOX could be a novel treatment for this condition. |
| doi_str_mv | 10.2337/db13-1896 |
| format | Article |
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Arachidonate 12/15-lipoxygenase (LOX) has been suggested to play an important role in atherogenesis and heart failure. However, the role of 12/15-LOX in diabetic cardiomyopathy has not been examined. In this study, we investigated the effects of cardiac 12/15-LOX on diabetic cardiomyopathy. We created streptozotocin (STZ)-induced diabetic mice and compared them with Alox15-deficient mice. Expression of 12/15-LOX and inflammatory cytokines such as tumor necrosis factor (TNF)-α and nuclear factor (NF)-κB were upregulated in STZ-induced diabetic hearts. Disruption of 12/15-LOX significantly improved STZ-induced cardiac dysfunction and fibrosis. Moreover, deletion of 12/15-LOX inhibited the increases of TNF-α and NF-κB as well as the production of STZ-induced reactive oxygen species in the heart. Administration of N-acetylcysteine in diabetic mice prevented STZ-induced cardiac fibrosis. Neonatal cultured cardiomyocytes exposed to high glucose conditions induced the expression of 12/15-LOX as well as TNF-α, NF-κB, and collagen markers. These increases were inhibited by treatment of the 12/15-LOX inhibitor. Our results suggest that cardiac 12/15-LOX-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy and that inhibition of 12/15-LOX could be a novel treatment for this condition.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db13-1896</identifier><identifier>PMID: 25187369</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng ; jpn</language><publisher>United States: American Diabetes Association</publisher><subject>Animals ; Arachidonate 12-Lipoxygenase - genetics ; Arachidonate 12-Lipoxygenase - metabolism ; Arachidonate 15-Lipoxygenase - genetics ; Arachidonate 15-Lipoxygenase - metabolism ; Blood Glucose ; Cardiomyopathy ; Diabetes ; Diabetes Mellitus, Experimental - complications ; Diabetic Cardiomyopathies - etiology ; Diabetic Cardiomyopathies - metabolism ; Fibrosis - etiology ; Gene Expression Regulation, Enzymologic ; Glucose ; Heart failure ; Hyperglycemia - complications ; Inflammation - metabolism ; Mice ; Mice, Knockout ; Oxidative stress ; Oxidative Stress - physiology ; Rodents ; TNF inhibitors ; Up-Regulation</subject><ispartof>Diabetes (New York, N.Y.), 2015-02, Vol.64 (2), p.618-630</ispartof><rights>2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.</rights><rights>Copyright American Diabetes Association Feb 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c498t-ccc18edffb6c114051366533aad5e8d1c3a5363949a7676d88da87c04a1515673</citedby><cites>FETCH-LOGICAL-c498t-ccc18edffb6c114051366533aad5e8d1c3a5363949a7676d88da87c04a1515673</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25187369$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Suzuki, Hirofumi</creatorcontrib><creatorcontrib>Kayama, Yosuke</creatorcontrib><creatorcontrib>Sakamoto, Masaya</creatorcontrib><creatorcontrib>Iuchi, Hiroyuki</creatorcontrib><creatorcontrib>Shimizu, Ippei</creatorcontrib><creatorcontrib>Yoshino, Takuya</creatorcontrib><creatorcontrib>Katoh, Daisuke</creatorcontrib><creatorcontrib>Nagoshi, Tomohisa</creatorcontrib><creatorcontrib>Tojo, Katsuyoshi</creatorcontrib><creatorcontrib>Minamino, Tohru</creatorcontrib><creatorcontrib>Yoshimura, Michihiro</creatorcontrib><creatorcontrib>Utsunomiya, Kazunori</creatorcontrib><title>Arachidonate 12/15-lipoxygenase-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Diabetes affects cardiac structure and function, and it has been suggested that diabetes leads to cardiomyopathy. Arachidonate 12/15-lipoxygenase (LOX) has been suggested to play an important role in atherogenesis and heart failure. However, the role of 12/15-LOX in diabetic cardiomyopathy has not been examined. In this study, we investigated the effects of cardiac 12/15-LOX on diabetic cardiomyopathy. We created streptozotocin (STZ)-induced diabetic mice and compared them with Alox15-deficient mice. Expression of 12/15-LOX and inflammatory cytokines such as tumor necrosis factor (TNF)-α and nuclear factor (NF)-κB were upregulated in STZ-induced diabetic hearts. Disruption of 12/15-LOX significantly improved STZ-induced cardiac dysfunction and fibrosis. Moreover, deletion of 12/15-LOX inhibited the increases of TNF-α and NF-κB as well as the production of STZ-induced reactive oxygen species in the heart. Administration of N-acetylcysteine in diabetic mice prevented STZ-induced cardiac fibrosis. Neonatal cultured cardiomyocytes exposed to high glucose conditions induced the expression of 12/15-LOX as well as TNF-α, NF-κB, and collagen markers. These increases were inhibited by treatment of the 12/15-LOX inhibitor. Our results suggest that cardiac 12/15-LOX-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy and that inhibition of 12/15-LOX could be a novel treatment for this condition.</description><subject>Animals</subject><subject>Arachidonate 12-Lipoxygenase - genetics</subject><subject>Arachidonate 12-Lipoxygenase - metabolism</subject><subject>Arachidonate 15-Lipoxygenase - genetics</subject><subject>Arachidonate 15-Lipoxygenase - metabolism</subject><subject>Blood Glucose</subject><subject>Cardiomyopathy</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Experimental - complications</subject><subject>Diabetic Cardiomyopathies - etiology</subject><subject>Diabetic Cardiomyopathies - metabolism</subject><subject>Fibrosis - etiology</subject><subject>Gene Expression Regulation, Enzymologic</subject><subject>Glucose</subject><subject>Heart failure</subject><subject>Hyperglycemia - complications</subject><subject>Inflammation - metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - physiology</subject><subject>Rodents</subject><subject>TNF inhibitors</subject><subject>Up-Regulation</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpd0U1r3DAQBmBRGppN2kP_QBH00hycaCzr6xhCvyDQSwq9mVlp3FWwLVeyl-y9PzzeJu2hzGEYeHgZeBl7C-KyltJchS3ICqzTL9gGnHSVrM2Pl2wjBNQVGGdO2Vkp90IIvc4rdlorsEZqt2G_rzP6XQxpxJk41Fegqj5O6eHwk0YsVMUxLJ4Cj2PX4zDgHNPIcQw8PcSwXnviZc5UCsdMq9qnfv-H83lHPNCe-jQNNM48dTxE3NIcPfeYQ0zDIU047w6v2UmHfaE3z_ucff_08e7mS3X77fPXm-vbyjfOzpX3HiyFrttqD9AIBVJrJSViUGQDeIlKaukah0YbHawNaI0XDYICpY08Zx-ecqecfi1U5naIxVPf40hpKS1oVUtrGyVW-v4_ep-WPK7fraqxzjoD9aounpTPqZRMXTvlOGA-tCDaYzXtsZr2WM1q3z0nLtuBwj_5twv5CJO4ims</recordid><startdate>20150201</startdate><enddate>20150201</enddate><creator>Suzuki, Hirofumi</creator><creator>Kayama, Yosuke</creator><creator>Sakamoto, Masaya</creator><creator>Iuchi, Hiroyuki</creator><creator>Shimizu, Ippei</creator><creator>Yoshino, Takuya</creator><creator>Katoh, Daisuke</creator><creator>Nagoshi, Tomohisa</creator><creator>Tojo, Katsuyoshi</creator><creator>Minamino, Tohru</creator><creator>Yoshimura, Michihiro</creator><creator>Utsunomiya, Kazunori</creator><general>American Diabetes Association</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>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>20150201</creationdate><title>Arachidonate 12/15-lipoxygenase-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy</title><author>Suzuki, Hirofumi ; Kayama, Yosuke ; Sakamoto, Masaya ; Iuchi, Hiroyuki ; Shimizu, Ippei ; Yoshino, Takuya ; Katoh, Daisuke ; Nagoshi, Tomohisa ; Tojo, Katsuyoshi ; Minamino, Tohru ; Yoshimura, Michihiro ; Utsunomiya, Kazunori</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c498t-ccc18edffb6c114051366533aad5e8d1c3a5363949a7676d88da87c04a1515673</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng ; jpn</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Arachidonate 12-Lipoxygenase - genetics</topic><topic>Arachidonate 12-Lipoxygenase - metabolism</topic><topic>Arachidonate 15-Lipoxygenase - genetics</topic><topic>Arachidonate 15-Lipoxygenase - metabolism</topic><topic>Blood Glucose</topic><topic>Cardiomyopathy</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Experimental - complications</topic><topic>Diabetic Cardiomyopathies - etiology</topic><topic>Diabetic Cardiomyopathies - metabolism</topic><topic>Fibrosis - etiology</topic><topic>Gene Expression Regulation, Enzymologic</topic><topic>Glucose</topic><topic>Heart failure</topic><topic>Hyperglycemia - complications</topic><topic>Inflammation - metabolism</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Oxidative stress</topic><topic>Oxidative Stress - physiology</topic><topic>Rodents</topic><topic>TNF inhibitors</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Suzuki, Hirofumi</creatorcontrib><creatorcontrib>Kayama, Yosuke</creatorcontrib><creatorcontrib>Sakamoto, Masaya</creatorcontrib><creatorcontrib>Iuchi, Hiroyuki</creatorcontrib><creatorcontrib>Shimizu, Ippei</creatorcontrib><creatorcontrib>Yoshino, Takuya</creatorcontrib><creatorcontrib>Katoh, Daisuke</creatorcontrib><creatorcontrib>Nagoshi, Tomohisa</creatorcontrib><creatorcontrib>Tojo, Katsuyoshi</creatorcontrib><creatorcontrib>Minamino, Tohru</creatorcontrib><creatorcontrib>Yoshimura, Michihiro</creatorcontrib><creatorcontrib>Utsunomiya, Kazunori</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Suzuki, Hirofumi</au><au>Kayama, Yosuke</au><au>Sakamoto, Masaya</au><au>Iuchi, Hiroyuki</au><au>Shimizu, Ippei</au><au>Yoshino, Takuya</au><au>Katoh, Daisuke</au><au>Nagoshi, Tomohisa</au><au>Tojo, Katsuyoshi</au><au>Minamino, Tohru</au><au>Yoshimura, Michihiro</au><au>Utsunomiya, Kazunori</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Arachidonate 12/15-lipoxygenase-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2015-02-01</date><risdate>2015</risdate><volume>64</volume><issue>2</issue><spage>618</spage><epage>630</epage><pages>618-630</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Diabetes affects cardiac structure and function, and it has been suggested that diabetes leads to cardiomyopathy. Arachidonate 12/15-lipoxygenase (LOX) has been suggested to play an important role in atherogenesis and heart failure. However, the role of 12/15-LOX in diabetic cardiomyopathy has not been examined. In this study, we investigated the effects of cardiac 12/15-LOX on diabetic cardiomyopathy. We created streptozotocin (STZ)-induced diabetic mice and compared them with Alox15-deficient mice. Expression of 12/15-LOX and inflammatory cytokines such as tumor necrosis factor (TNF)-α and nuclear factor (NF)-κB were upregulated in STZ-induced diabetic hearts. Disruption of 12/15-LOX significantly improved STZ-induced cardiac dysfunction and fibrosis. Moreover, deletion of 12/15-LOX inhibited the increases of TNF-α and NF-κB as well as the production of STZ-induced reactive oxygen species in the heart. Administration of N-acetylcysteine in diabetic mice prevented STZ-induced cardiac fibrosis. Neonatal cultured cardiomyocytes exposed to high glucose conditions induced the expression of 12/15-LOX as well as TNF-α, NF-κB, and collagen markers. These increases were inhibited by treatment of the 12/15-LOX inhibitor. Our results suggest that cardiac 12/15-LOX-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy and that inhibition of 12/15-LOX could be a novel treatment for this condition.</abstract><cop>United States</cop><pub>American Diabetes Association</pub><pmid>25187369</pmid><doi>10.2337/db13-1896</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Arachidonate 12-Lipoxygenase - genetics Arachidonate 12-Lipoxygenase - metabolism Arachidonate 15-Lipoxygenase - genetics Arachidonate 15-Lipoxygenase - metabolism Blood Glucose Cardiomyopathy Diabetes Diabetes Mellitus, Experimental - complications Diabetic Cardiomyopathies - etiology Diabetic Cardiomyopathies - metabolism Fibrosis - etiology Gene Expression Regulation, Enzymologic Glucose Heart failure Hyperglycemia - complications Inflammation - metabolism Mice Mice, Knockout Oxidative stress Oxidative Stress - physiology Rodents TNF inhibitors Up-Regulation |
| title | Arachidonate 12/15-lipoxygenase-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy |
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