p53 plays a crucial role in endothelial dysfunction associated with hyperglycemia and ischemia
[Display omitted] p53 is a guardian of the genome that protects against carcinogenesis. There is accumulating evidence that p53 is activated with aging. Such activation has been reported to contribute to various age-associated pathologies, but its role in vascular dysfunction is largely unknown. The...
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Veröffentlicht in: | Journal of molecular and cellular cardiology 2019-04, Vol.129, p.105-117 |
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creator | Yokoyama, Masataka Shimizu, Ippei Nagasawa, Ayako Yoshida, Yohko Katsuumi, Goro Wakasugi, Takayuki Hayashi, Yuka Ikegami, Ryutaro Suda, Masayoshi Ota, Yusuke Okada, Sho Fruttiger, Marcus Kobayashi, Yoshio Tsuchida, Masanori Kubota, Yoshiaki Minamino, Tohru |
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p53 is a guardian of the genome that protects against carcinogenesis. There is accumulating evidence that p53 is activated with aging. Such activation has been reported to contribute to various age-associated pathologies, but its role in vascular dysfunction is largely unknown. The aim of this study was to investigate whether activation of endothelial p53 has a pathological effect in relation to endothelial function. We established endothelial p53 loss-of-function and gain-of-function models by breeding endothelial-cell specific Cre mice with floxed Trp53 or floxed Mdm2/Mdm4 mice, respectively. Then we induced diabetes by injection of streptozotocin. In the diabetic state, endothelial p53 expression was markedly up-regulated and endothelium-dependent vasodilatation was significantly impaired. Impairment of vasodilatation was significantly ameliorated in endothelial p53 knockout (EC-p53 KO) mice, and deletion of endothelial p53 also significantly enhanced the induction of angiogenesis by ischemia. Conversely, activation of endothelial p53 by deleting Mdm2/Mdm4 reduced both endothelium-dependent vasodilatation and ischemia-induced angiogenesis. Introduction of p53 into human endothelial cells up-regulated the expression of phosphatase and tensin homolog (PTEN), thereby reducing phospho-eNOS levels. Consistent with these results, the beneficial impact of endothelial p53 deletion on endothelial function was attenuated in EC-p53 KO mice with an eNOS-deficient background. These results show that endothelial p53 negatively regulates endothelium-dependent vasodilatation and ischemia-induced angiogenesis, suggesting that inhibition of endothelial p53 could be a novel therapeutic target in patients with metabolic disorders.
•Endothelial p53 negatively regulates eNOS phosphorylation and impairs endothelium-dependent vasodilatation.•p53-induced inhibition of eNOS is mediated by PTEN transactivation, contributing to diabetic endothelial dysfunction.•Inhibition of endothelial p53 activation enhances ischemia-induced angiogenesis.•Overexpression of p53 by Mdm2/Mdm4 deletion impairs endothelial function. |
doi_str_mv | 10.1016/j.yjmcc.2019.02.010 |
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p53 is a guardian of the genome that protects against carcinogenesis. There is accumulating evidence that p53 is activated with aging. Such activation has been reported to contribute to various age-associated pathologies, but its role in vascular dysfunction is largely unknown. The aim of this study was to investigate whether activation of endothelial p53 has a pathological effect in relation to endothelial function. We established endothelial p53 loss-of-function and gain-of-function models by breeding endothelial-cell specific Cre mice with floxed Trp53 or floxed Mdm2/Mdm4 mice, respectively. Then we induced diabetes by injection of streptozotocin. In the diabetic state, endothelial p53 expression was markedly up-regulated and endothelium-dependent vasodilatation was significantly impaired. Impairment of vasodilatation was significantly ameliorated in endothelial p53 knockout (EC-p53 KO) mice, and deletion of endothelial p53 also significantly enhanced the induction of angiogenesis by ischemia. Conversely, activation of endothelial p53 by deleting Mdm2/Mdm4 reduced both endothelium-dependent vasodilatation and ischemia-induced angiogenesis. Introduction of p53 into human endothelial cells up-regulated the expression of phosphatase and tensin homolog (PTEN), thereby reducing phospho-eNOS levels. Consistent with these results, the beneficial impact of endothelial p53 deletion on endothelial function was attenuated in EC-p53 KO mice with an eNOS-deficient background. These results show that endothelial p53 negatively regulates endothelium-dependent vasodilatation and ischemia-induced angiogenesis, suggesting that inhibition of endothelial p53 could be a novel therapeutic target in patients with metabolic disorders.
•Endothelial p53 negatively regulates eNOS phosphorylation and impairs endothelium-dependent vasodilatation.•p53-induced inhibition of eNOS is mediated by PTEN transactivation, contributing to diabetic endothelial dysfunction.•Inhibition of endothelial p53 activation enhances ischemia-induced angiogenesis.•Overexpression of p53 by Mdm2/Mdm4 deletion impairs endothelial function.</description><identifier>ISSN: 0022-2828</identifier><identifier>EISSN: 1095-8584</identifier><identifier>DOI: 10.1016/j.yjmcc.2019.02.010</identifier><identifier>PMID: 30790589</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Angiogenesis ; Endothelium ; Nitric oxide ; Vascular disease</subject><ispartof>Journal of molecular and cellular cardiology, 2019-04, Vol.129, p.105-117</ispartof><rights>2019 Elsevier Ltd</rights><rights>Copyright © 2019 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c404t-b61b8e313be5eb2bfc90f3cc9bd44a702c5735293edbb5a2ac79451cdf80f68a3</citedby><cites>FETCH-LOGICAL-c404t-b61b8e313be5eb2bfc90f3cc9bd44a702c5735293edbb5a2ac79451cdf80f68a3</cites><orcidid>0000-0003-1627-6151</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.yjmcc.2019.02.010$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30790589$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yokoyama, Masataka</creatorcontrib><creatorcontrib>Shimizu, Ippei</creatorcontrib><creatorcontrib>Nagasawa, Ayako</creatorcontrib><creatorcontrib>Yoshida, Yohko</creatorcontrib><creatorcontrib>Katsuumi, Goro</creatorcontrib><creatorcontrib>Wakasugi, Takayuki</creatorcontrib><creatorcontrib>Hayashi, Yuka</creatorcontrib><creatorcontrib>Ikegami, Ryutaro</creatorcontrib><creatorcontrib>Suda, Masayoshi</creatorcontrib><creatorcontrib>Ota, Yusuke</creatorcontrib><creatorcontrib>Okada, Sho</creatorcontrib><creatorcontrib>Fruttiger, Marcus</creatorcontrib><creatorcontrib>Kobayashi, Yoshio</creatorcontrib><creatorcontrib>Tsuchida, Masanori</creatorcontrib><creatorcontrib>Kubota, Yoshiaki</creatorcontrib><creatorcontrib>Minamino, Tohru</creatorcontrib><title>p53 plays a crucial role in endothelial dysfunction associated with hyperglycemia and ischemia</title><title>Journal of molecular and cellular cardiology</title><addtitle>J Mol Cell Cardiol</addtitle><description>[Display omitted]
p53 is a guardian of the genome that protects against carcinogenesis. There is accumulating evidence that p53 is activated with aging. Such activation has been reported to contribute to various age-associated pathologies, but its role in vascular dysfunction is largely unknown. The aim of this study was to investigate whether activation of endothelial p53 has a pathological effect in relation to endothelial function. We established endothelial p53 loss-of-function and gain-of-function models by breeding endothelial-cell specific Cre mice with floxed Trp53 or floxed Mdm2/Mdm4 mice, respectively. Then we induced diabetes by injection of streptozotocin. In the diabetic state, endothelial p53 expression was markedly up-regulated and endothelium-dependent vasodilatation was significantly impaired. Impairment of vasodilatation was significantly ameliorated in endothelial p53 knockout (EC-p53 KO) mice, and deletion of endothelial p53 also significantly enhanced the induction of angiogenesis by ischemia. Conversely, activation of endothelial p53 by deleting Mdm2/Mdm4 reduced both endothelium-dependent vasodilatation and ischemia-induced angiogenesis. Introduction of p53 into human endothelial cells up-regulated the expression of phosphatase and tensin homolog (PTEN), thereby reducing phospho-eNOS levels. Consistent with these results, the beneficial impact of endothelial p53 deletion on endothelial function was attenuated in EC-p53 KO mice with an eNOS-deficient background. These results show that endothelial p53 negatively regulates endothelium-dependent vasodilatation and ischemia-induced angiogenesis, suggesting that inhibition of endothelial p53 could be a novel therapeutic target in patients with metabolic disorders.
•Endothelial p53 negatively regulates eNOS phosphorylation and impairs endothelium-dependent vasodilatation.•p53-induced inhibition of eNOS is mediated by PTEN transactivation, contributing to diabetic endothelial dysfunction.•Inhibition of endothelial p53 activation enhances ischemia-induced angiogenesis.•Overexpression of p53 by Mdm2/Mdm4 deletion impairs endothelial function.</description><subject>Angiogenesis</subject><subject>Endothelium</subject><subject>Nitric oxide</subject><subject>Vascular disease</subject><issn>0022-2828</issn><issn>1095-8584</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp9kDuP1DAQgC0E4vYOfgESckmTMLbjJC4o0OmAk06igRbLHk9Yr_LCTkD592TZg5JqNKNvXh9jrwSUAkT99lRupwGxlCBMCbIEAU_YQYDRRavb6ik7AEhZyFa2V-w65xMAmEqp5-xKQWNAt-bAvs1a8bl3W-aOY1oxup6nqSceR05jmJYj9eda2HK3jrjEaeQu52kHFwr8V1yO_LjNlL73G9IQHXdj4DHj8Zy8YM8612d6-Rhv2NcPd19uPxUPnz_e375_KLCCail8LXxLSihPmrz0HRroFKLxoapcAxJ1o7Q0ioL32kmHjam0wNC10NWtUzfszWXunKYfK-XFDvsJ1PdupGnNVopW61qZpt5RdUExTTkn6uyc4uDSZgXYs1h7sn_E2rNYC9LuYveu148LVj9Q-Nfz1-QOvLsAtL_5M1KyGSONSCEmwsWGKf53wW8IyoxH</recordid><startdate>201904</startdate><enddate>201904</enddate><creator>Yokoyama, Masataka</creator><creator>Shimizu, Ippei</creator><creator>Nagasawa, Ayako</creator><creator>Yoshida, Yohko</creator><creator>Katsuumi, Goro</creator><creator>Wakasugi, Takayuki</creator><creator>Hayashi, Yuka</creator><creator>Ikegami, Ryutaro</creator><creator>Suda, Masayoshi</creator><creator>Ota, Yusuke</creator><creator>Okada, Sho</creator><creator>Fruttiger, Marcus</creator><creator>Kobayashi, Yoshio</creator><creator>Tsuchida, Masanori</creator><creator>Kubota, Yoshiaki</creator><creator>Minamino, Tohru</creator><general>Elsevier Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-1627-6151</orcidid></search><sort><creationdate>201904</creationdate><title>p53 plays a crucial role in endothelial dysfunction associated with hyperglycemia and ischemia</title><author>Yokoyama, Masataka ; Shimizu, Ippei ; Nagasawa, Ayako ; Yoshida, Yohko ; Katsuumi, Goro ; Wakasugi, Takayuki ; Hayashi, Yuka ; Ikegami, Ryutaro ; Suda, Masayoshi ; Ota, Yusuke ; Okada, Sho ; Fruttiger, Marcus ; Kobayashi, Yoshio ; Tsuchida, Masanori ; Kubota, Yoshiaki ; Minamino, Tohru</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c404t-b61b8e313be5eb2bfc90f3cc9bd44a702c5735293edbb5a2ac79451cdf80f68a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Angiogenesis</topic><topic>Endothelium</topic><topic>Nitric oxide</topic><topic>Vascular disease</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yokoyama, Masataka</creatorcontrib><creatorcontrib>Shimizu, Ippei</creatorcontrib><creatorcontrib>Nagasawa, Ayako</creatorcontrib><creatorcontrib>Yoshida, Yohko</creatorcontrib><creatorcontrib>Katsuumi, Goro</creatorcontrib><creatorcontrib>Wakasugi, Takayuki</creatorcontrib><creatorcontrib>Hayashi, Yuka</creatorcontrib><creatorcontrib>Ikegami, Ryutaro</creatorcontrib><creatorcontrib>Suda, Masayoshi</creatorcontrib><creatorcontrib>Ota, Yusuke</creatorcontrib><creatorcontrib>Okada, Sho</creatorcontrib><creatorcontrib>Fruttiger, Marcus</creatorcontrib><creatorcontrib>Kobayashi, Yoshio</creatorcontrib><creatorcontrib>Tsuchida, Masanori</creatorcontrib><creatorcontrib>Kubota, Yoshiaki</creatorcontrib><creatorcontrib>Minamino, Tohru</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of molecular and cellular cardiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yokoyama, Masataka</au><au>Shimizu, Ippei</au><au>Nagasawa, Ayako</au><au>Yoshida, Yohko</au><au>Katsuumi, Goro</au><au>Wakasugi, Takayuki</au><au>Hayashi, Yuka</au><au>Ikegami, Ryutaro</au><au>Suda, Masayoshi</au><au>Ota, Yusuke</au><au>Okada, Sho</au><au>Fruttiger, Marcus</au><au>Kobayashi, Yoshio</au><au>Tsuchida, Masanori</au><au>Kubota, Yoshiaki</au><au>Minamino, Tohru</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>p53 plays a crucial role in endothelial dysfunction associated with hyperglycemia and ischemia</atitle><jtitle>Journal of molecular and cellular cardiology</jtitle><addtitle>J Mol Cell Cardiol</addtitle><date>2019-04</date><risdate>2019</risdate><volume>129</volume><spage>105</spage><epage>117</epage><pages>105-117</pages><issn>0022-2828</issn><eissn>1095-8584</eissn><abstract>[Display omitted]
p53 is a guardian of the genome that protects against carcinogenesis. There is accumulating evidence that p53 is activated with aging. Such activation has been reported to contribute to various age-associated pathologies, but its role in vascular dysfunction is largely unknown. The aim of this study was to investigate whether activation of endothelial p53 has a pathological effect in relation to endothelial function. We established endothelial p53 loss-of-function and gain-of-function models by breeding endothelial-cell specific Cre mice with floxed Trp53 or floxed Mdm2/Mdm4 mice, respectively. Then we induced diabetes by injection of streptozotocin. In the diabetic state, endothelial p53 expression was markedly up-regulated and endothelium-dependent vasodilatation was significantly impaired. Impairment of vasodilatation was significantly ameliorated in endothelial p53 knockout (EC-p53 KO) mice, and deletion of endothelial p53 also significantly enhanced the induction of angiogenesis by ischemia. Conversely, activation of endothelial p53 by deleting Mdm2/Mdm4 reduced both endothelium-dependent vasodilatation and ischemia-induced angiogenesis. Introduction of p53 into human endothelial cells up-regulated the expression of phosphatase and tensin homolog (PTEN), thereby reducing phospho-eNOS levels. Consistent with these results, the beneficial impact of endothelial p53 deletion on endothelial function was attenuated in EC-p53 KO mice with an eNOS-deficient background. These results show that endothelial p53 negatively regulates endothelium-dependent vasodilatation and ischemia-induced angiogenesis, suggesting that inhibition of endothelial p53 could be a novel therapeutic target in patients with metabolic disorders.
•Endothelial p53 negatively regulates eNOS phosphorylation and impairs endothelium-dependent vasodilatation.•p53-induced inhibition of eNOS is mediated by PTEN transactivation, contributing to diabetic endothelial dysfunction.•Inhibition of endothelial p53 activation enhances ischemia-induced angiogenesis.•Overexpression of p53 by Mdm2/Mdm4 deletion impairs endothelial function.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>30790589</pmid><doi>10.1016/j.yjmcc.2019.02.010</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0003-1627-6151</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Angiogenesis Endothelium Nitric oxide Vascular disease |
title | p53 plays a crucial role in endothelial dysfunction associated with hyperglycemia and ischemia |
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