The Mammalian Target of Rapamycin and DNA methyltransferase 1 axis mediates vascular endothelial dysfunction in response to disturbed flow
The earliest atherosclerotic lesions preferentially develop in arterial regions experienced disturbed blood flow, which induces endothelial expression of pro-atherogenic genes and the subsequent endothelial dysfunction. Our previous study has demonstrated an up-regulation of DNA methyltransferase 1...
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| Veröffentlicht in: | Scientific reports 2017-11, Vol.7 (1), p.14996-12, Article 14996 |
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| creator | Zhang, Yun-Peng Huang, Yi-Tao Huang, Tse-Shun Pang, Wei Zhu, Juan-Juan Liu, Yue-Feng Tang, Run-Ze Zhao, Chuan-Rong Yao, Wei-Juan Li, Yi-Shuan Chien, Shu Zhou, Jing |
| description | The earliest atherosclerotic lesions preferentially develop in arterial regions experienced disturbed blood flow, which induces endothelial expression of pro-atherogenic genes and the subsequent endothelial dysfunction. Our previous study has demonstrated an up-regulation of DNA methyltransferase 1 (DNMT1) and a global hypermethylation in vascular endothelium subjected to disturbed flow. Here, we determined that DNMT1-specific inhibition in arterial wall ameliorates the disturbed flow-induced atherosclerosis through, at least in part, targeting cell cycle regulator cyclin A and connective tissue growth factor (CTGF). We identified the signaling pathways mediating the flow-induction of DNMT1. Inhibition of the mammalian target of rapamycin (mTOR) suppressed the DNMT1 up-regulation both
in vitro
and
in vivo
. Together, our results demonstrate that disturbed flow influences endothelial function and induces atherosclerosis in an mTOR/DNMT1-dependent manner. The conclusions obtained from this study might facilitate further evaluation of the epigenetic regulation of endothelial function during the pathological development of atherosclerosis and offer novel prevention and therapeutic targets of this disease. |
| doi_str_mv | 10.1038/s41598-017-15387-5 |
| format | Article |
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in vitro
and
in vivo
. Together, our results demonstrate that disturbed flow influences endothelial function and induces atherosclerosis in an mTOR/DNMT1-dependent manner. The conclusions obtained from this study might facilitate further evaluation of the epigenetic regulation of endothelial function during the pathological development of atherosclerosis and offer novel prevention and therapeutic targets of this disease.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-017-15387-5</identifier><identifier>PMID: 29118325</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/106 ; 13/107 ; 13/109 ; 13/95 ; 14/63 ; 38/77 ; 38/89 ; 631/443/592/75 ; 631/80/304 ; 692/420/256/2515 ; Animals ; Arteries - pathology ; Arteries - physiopathology ; Arteriosclerosis ; Atherosclerosis ; Atherosclerosis - genetics ; Atherosclerosis - pathology ; Atherosclerosis - physiopathology ; Blood flow ; Cattle ; Cell cycle ; Circulatory system ; Connective tissue growth factor ; Connective Tissue Growth Factor - genetics ; Connective Tissue Growth Factor - metabolism ; Cyclin A ; Cyclin A - genetics ; Cyclin A - metabolism ; Deoxyribonucleic acid ; Disease Models, Animal ; DNA ; DNA (Cytosine-5-)-Methyltransferase 1 - metabolism ; DNA Methylation - physiology ; DNA methyltransferase ; DNMT1 protein ; Endothelium ; Endothelium, Vascular - pathology ; Epigenesis, Genetic - physiology ; Hemorheology - physiology ; Human Umbilical Vein Endothelial Cells ; Humanities and Social Sciences ; Humans ; Mammals ; Mice ; Mice, Inbred C57BL ; Mice, Knockout, ApoE ; multidisciplinary ; Promoter Regions, Genetic - genetics ; Rapamycin ; Science ; Science (multidisciplinary) ; TOR protein ; TOR Serine-Threonine Kinases - metabolism</subject><ispartof>Scientific reports, 2017-11, Vol.7 (1), p.14996-12, Article 14996</ispartof><rights>The Author(s) 2017</rights><rights>2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-f7b90cca91966c798f899924993995e523f9c5ccaa6b7af5d864445b4980b503</citedby><cites>FETCH-LOGICAL-c474t-f7b90cca91966c798f899924993995e523f9c5ccaa6b7af5d864445b4980b503</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/PMC5678172/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678172/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,27929,27930,41125,42194,51581,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29118325$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Yun-Peng</creatorcontrib><creatorcontrib>Huang, Yi-Tao</creatorcontrib><creatorcontrib>Huang, Tse-Shun</creatorcontrib><creatorcontrib>Pang, Wei</creatorcontrib><creatorcontrib>Zhu, Juan-Juan</creatorcontrib><creatorcontrib>Liu, Yue-Feng</creatorcontrib><creatorcontrib>Tang, Run-Ze</creatorcontrib><creatorcontrib>Zhao, Chuan-Rong</creatorcontrib><creatorcontrib>Yao, Wei-Juan</creatorcontrib><creatorcontrib>Li, Yi-Shuan</creatorcontrib><creatorcontrib>Chien, Shu</creatorcontrib><creatorcontrib>Zhou, Jing</creatorcontrib><title>The Mammalian Target of Rapamycin and DNA methyltransferase 1 axis mediates vascular endothelial dysfunction in response to disturbed flow</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>The earliest atherosclerotic lesions preferentially develop in arterial regions experienced disturbed blood flow, which induces endothelial expression of pro-atherogenic genes and the subsequent endothelial dysfunction. Our previous study has demonstrated an up-regulation of DNA methyltransferase 1 (DNMT1) and a global hypermethylation in vascular endothelium subjected to disturbed flow. Here, we determined that DNMT1-specific inhibition in arterial wall ameliorates the disturbed flow-induced atherosclerosis through, at least in part, targeting cell cycle regulator cyclin A and connective tissue growth factor (CTGF). We identified the signaling pathways mediating the flow-induction of DNMT1. Inhibition of the mammalian target of rapamycin (mTOR) suppressed the DNMT1 up-regulation both
in vitro
and
in vivo
. Together, our results demonstrate that disturbed flow influences endothelial function and induces atherosclerosis in an mTOR/DNMT1-dependent manner. The conclusions obtained from this study might facilitate further evaluation of the epigenetic regulation of endothelial function during the pathological development of atherosclerosis and offer novel prevention and therapeutic targets of this disease.</description><subject>13/106</subject><subject>13/107</subject><subject>13/109</subject><subject>13/95</subject><subject>14/63</subject><subject>38/77</subject><subject>38/89</subject><subject>631/443/592/75</subject><subject>631/80/304</subject><subject>692/420/256/2515</subject><subject>Animals</subject><subject>Arteries - pathology</subject><subject>Arteries - physiopathology</subject><subject>Arteriosclerosis</subject><subject>Atherosclerosis</subject><subject>Atherosclerosis - genetics</subject><subject>Atherosclerosis - pathology</subject><subject>Atherosclerosis - physiopathology</subject><subject>Blood flow</subject><subject>Cattle</subject><subject>Cell cycle</subject><subject>Circulatory system</subject><subject>Connective tissue growth factor</subject><subject>Connective Tissue Growth Factor - genetics</subject><subject>Connective Tissue Growth Factor - metabolism</subject><subject>Cyclin A</subject><subject>Cyclin A - genetics</subject><subject>Cyclin A - metabolism</subject><subject>Deoxyribonucleic acid</subject><subject>Disease Models, Animal</subject><subject>DNA</subject><subject>DNA (Cytosine-5-)-Methyltransferase 1 - metabolism</subject><subject>DNA Methylation - physiology</subject><subject>DNA methyltransferase</subject><subject>DNMT1 protein</subject><subject>Endothelium</subject><subject>Endothelium, Vascular - pathology</subject><subject>Epigenesis, Genetic - physiology</subject><subject>Hemorheology - physiology</subject><subject>Human Umbilical Vein Endothelial Cells</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Mammals</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout, ApoE</subject><subject>multidisciplinary</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Rapamycin</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases - 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physiology</topic><topic>Human Umbilical Vein Endothelial Cells</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Mammals</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout, ApoE</topic><topic>multidisciplinary</topic><topic>Promoter Regions, Genetic - genetics</topic><topic>Rapamycin</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>TOR protein</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Yun-Peng</creatorcontrib><creatorcontrib>Huang, Yi-Tao</creatorcontrib><creatorcontrib>Huang, Tse-Shun</creatorcontrib><creatorcontrib>Pang, Wei</creatorcontrib><creatorcontrib>Zhu, Juan-Juan</creatorcontrib><creatorcontrib>Liu, Yue-Feng</creatorcontrib><creatorcontrib>Tang, Run-Ze</creatorcontrib><creatorcontrib>Zhao, Chuan-Rong</creatorcontrib><creatorcontrib>Yao, Wei-Juan</creatorcontrib><creatorcontrib>Li, Yi-Shuan</creatorcontrib><creatorcontrib>Chien, Shu</creatorcontrib><creatorcontrib>Zhou, Jing</creatorcontrib><collection>Springer Nature OA/Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech 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>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database (ProQuest)</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Yun-Peng</au><au>Huang, Yi-Tao</au><au>Huang, Tse-Shun</au><au>Pang, Wei</au><au>Zhu, Juan-Juan</au><au>Liu, Yue-Feng</au><au>Tang, Run-Ze</au><au>Zhao, Chuan-Rong</au><au>Yao, Wei-Juan</au><au>Li, Yi-Shuan</au><au>Chien, Shu</au><au>Zhou, Jing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Mammalian Target of Rapamycin and DNA methyltransferase 1 axis mediates vascular endothelial dysfunction in response to disturbed flow</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2017-11-08</date><risdate>2017</risdate><volume>7</volume><issue>1</issue><spage>14996</spage><epage>12</epage><pages>14996-12</pages><artnum>14996</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>The earliest atherosclerotic lesions preferentially develop in arterial regions experienced disturbed blood flow, which induces endothelial expression of pro-atherogenic genes and the subsequent endothelial dysfunction. Our previous study has demonstrated an up-regulation of DNA methyltransferase 1 (DNMT1) and a global hypermethylation in vascular endothelium subjected to disturbed flow. Here, we determined that DNMT1-specific inhibition in arterial wall ameliorates the disturbed flow-induced atherosclerosis through, at least in part, targeting cell cycle regulator cyclin A and connective tissue growth factor (CTGF). We identified the signaling pathways mediating the flow-induction of DNMT1. Inhibition of the mammalian target of rapamycin (mTOR) suppressed the DNMT1 up-regulation both
in vitro
and
in vivo
. Together, our results demonstrate that disturbed flow influences endothelial function and induces atherosclerosis in an mTOR/DNMT1-dependent manner. The conclusions obtained from this study might facilitate further evaluation of the epigenetic regulation of endothelial function during the pathological development of atherosclerosis and offer novel prevention and therapeutic targets of this disease.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29118325</pmid><doi>10.1038/s41598-017-15387-5</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13/106 13/107 13/109 13/95 14/63 38/77 38/89 631/443/592/75 631/80/304 692/420/256/2515 Animals Arteries - pathology Arteries - physiopathology Arteriosclerosis Atherosclerosis Atherosclerosis - genetics Atherosclerosis - pathology Atherosclerosis - physiopathology Blood flow Cattle Cell cycle Circulatory system Connective tissue growth factor Connective Tissue Growth Factor - genetics Connective Tissue Growth Factor - metabolism Cyclin A Cyclin A - genetics Cyclin A - metabolism Deoxyribonucleic acid Disease Models, Animal DNA DNA (Cytosine-5-)-Methyltransferase 1 - metabolism DNA Methylation - physiology DNA methyltransferase DNMT1 protein Endothelium Endothelium, Vascular - pathology Epigenesis, Genetic - physiology Hemorheology - physiology Human Umbilical Vein Endothelial Cells Humanities and Social Sciences Humans Mammals Mice Mice, Inbred C57BL Mice, Knockout, ApoE multidisciplinary Promoter Regions, Genetic - genetics Rapamycin Science Science (multidisciplinary) TOR protein TOR Serine-Threonine Kinases - metabolism |
| title | The Mammalian Target of Rapamycin and DNA methyltransferase 1 axis mediates vascular endothelial dysfunction in response to disturbed flow |
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