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<!DOCTYPE html> <html lang="en" class="no-js"> <head> <meta charset="UTF-8"> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="applicable-device" content="pc,mobile"> <meta name="viewport" content="width=device-width, initial-scale=1"> <meta name="robots" content="max-image-preview:large"> <meta name="access" content="No"> <meta name="360-site-verification" content="1268d79b5e96aecf3ff2a7dac04ad990" /> <title>Targeted disruption of p53 attenuates doxorubicin-induced cardiac toxicity in mice | Molecular and Cellular Biochemistry </title> <meta name="twitter:site" content="@SpringerLink"/> <meta name="twitter:card" content="summary_large_image"/> <meta name="twitter:image:alt" content="Content cover image"/> <meta name="twitter:title" content="Targeted disruption of p53 attenuates doxorubicin-induced cardiac toxicity in mice"/> <meta name="twitter:description" content="Molecular and Cellular Biochemistry - Use of the chemotherapeutic agent doxorubicin (Dox) is limited by dose-dependent cardiotoxic effects. The molecular mechanism underlying these toxicities are..."/> <meta name="twitter:image" content="https://media.springernature.com/full/springer-static/cover-hires/journal/11010"/> <meta name="journal_id" content="11010"/> <meta name="dc.title" content="Targeted disruption of p53 attenuates doxorubicin-induced cardiac toxicity in mice"/> <meta name="dc.source" content="Molecular and Cellular Biochemistry 2005 273:1"/> <meta name="dc.format" content="text/html"/> <meta name="dc.publisher" content="Springer"/> <meta name="dc.type" content="OriginalPaper"/> <meta name="dc.language" content="En"/> <meta name="dc.copyright" content="2005 Springer Science + Business Media, Inc."/> <meta name="dc.rights" content="2005 Springer Science + Business Media, Inc."/> <meta name="dc.rightsAgent" content="journalpermissions@springernature.com"/> <meta name="dc.description" content="Use of the chemotherapeutic agent doxorubicin (Dox) is limited by dose-dependent cardiotoxic effects. The molecular mechanism underlying these toxicities are incompletely understood, but previous results have demonstrated that Dox induces p53 expression. Because p53 is an important regulator of the cell birth and death we hypothesized that targeted disruption of the p53 gene would attenuate Dox-induced cardiotoxicity. To test this, female 6–8 wk old C57BL wild-type (WT) or p53 knockout (p53 KO) mice were randomized to either saline or Dox 20 mg/kg via intraperitoneal injection. Animals were serially imaged with high-frequency (14 MHz) two-dimensional echocardiography. Measurements of left ventricle (LV) systolic function as assessed by fractional shortening (FS) demonstrated a decline in WT mice as early as 4 days after Dox injection and by 2 wk demonstrated a reduction of 31± 16% (P &lt; 0.05) from the baseline. In contrast, in p53 KO mice, LV FS was unchanged over the 2 wk period following Dox injection. Apoptosis of cardiac myocytes as measured by the TUNEL and ligase reactions were significantly increased at 24 h after Dox treatment in WT mice but not in p53 KO mice. After Dox injection, levels of myocardial glutathione and Cu/Zn superoxide dismutase were preserved in p53 KO mice, but not in WT animals. These observations suggest that p53 mediated signals are likely to play a significant role in Dox-induced cardiac toxicity and that they may modulate Dox-induced oxidative stress."/> <meta name="prism.issn" content="1573-4919"/> <meta name="prism.publicationName" content="Molecular and Cellular Biochemistry"/> <meta name="prism.volume" content="273"/> <meta name="prism.number" content="1"/> <meta name="prism.section" content="OriginalPaper"/> <meta name="prism.startingPage" content="25"/> <meta name="prism.endingPage" content="32"/> <meta name="prism.copyright" content="2005 Springer Science + Business Media, Inc."/> <meta name="prism.rightsAgent" content="journalpermissions@springernature.com"/> <meta name="prism.url" content="https://link.springer.com/article/10.1007/s11010-005-5905-8"/> <meta name="prism.doi" content="doi:10.1007/s11010-005-5905-8"/> <meta name="citation_pdf_url" content="https://link.springer.com/content/pdf/10.1007/s11010-005-5905-8.pdf"/> <meta name="citation_fulltext_html_url" content="https://link.springer.com/article/10.1007/s11010-005-5905-8"/> <meta name="citation_journal_title" content="Molecular and Cellular Biochemistry"/> <meta name="citation_journal_abbrev" content="Mol Cell Biochem"/> <meta name="citation_publisher" content="Kluwer Academic Publishers"/> <meta name="citation_issn" content="1573-4919"/> <meta name="citation_title" content="Targeted disruption of p53 attenuates doxorubicin-induced cardiac toxicity in mice"/> <meta name="citation_volume" content="273"/> <meta name="citation_issue" content="1"/> <meta name="citation_publication_date" content="2005/05"/> <meta name="citation_firstpage" content="25"/> <meta name="citation_lastpage" content="32"/> <meta name="citation_article_type" content="Article"/> <meta name="citation_language" content="en"/> <meta name="dc.identifier" content="doi:10.1007/s11010-005-5905-8"/> <meta name="DOI" content="10.1007/s11010-005-5905-8"/> <meta name="size" content="130290"/> <meta name="citation_doi" content="10.1007/s11010-005-5905-8"/> <meta name="citation_springer_api_url" content="http://api.springer.com/xmldata/jats?q=doi:10.1007/s11010-005-5905-8&api_key="/> <meta name="description" content="Use of the chemotherapeutic agent doxorubicin (Dox) is limited by dose-dependent cardiotoxic effects. The molecular mechanism underlying these toxicities a"/> <meta name="dc.creator" content="Shizukuda, Yukitaka"/> <meta name="dc.creator" content="Matoba, Satoaki"/> <meta name="dc.creator" content="Mian, Omar Y."/> <meta name="dc.creator" content="Nguyen, Tammy"/> <meta name="dc.creator" content="Hwang, Paul M."/> <meta name="dc.subject" content="Biochemistry, general"/> <meta name="dc.subject" content="Cardiology"/> <meta name="dc.subject" content="Cancer Research"/> <meta name="dc.subject" content="Medical Biochemistry"/> <meta name="citation_reference" content="citation_journal_title=Ann Intern Med; citation_title=Anthracycline-induced cardiotoxicity; citation_author=K Shan, AM Lincoff, JB Young; citation_volume=125; citation_publication_date=1996; citation_pages=47-58; citation_id=CR1"/> <meta name="citation_reference" content="citation_journal_title=An overview. 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citation_volume=3; citation_publication_date=2003; citation_pages=16-24; citation_doi=10.1186/1471-2210-3-16; citation_id=CR43"/> <meta name="citation_author" content="Shizukuda, Yukitaka"/> <meta name="citation_author_email" content="shizukuy@nhlbi.nih.gov"/> <meta name="citation_author_institution" content="Cardiovascular Branch, National Heart Lung, and Blood Institute, National Institutes of Health, Bethesda, USA"/> <meta name="citation_author_institution" content="Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda"/> <meta name="citation_author" content="Matoba, Satoaki"/> <meta name="citation_author_institution" content="Cardiovascular Branch, National Heart Lung, and Blood Institute, National Institutes of Health, Bethesda, USA"/> <meta name="citation_author" content="Mian, Omar Y."/> <meta name="citation_author_institution" content="Cardiovascular Branch, National Heart Lung, and Blood Institute, National Institutes of Health, Bethesda, USA"/> <meta name="citation_author" content="Nguyen, Tammy"/> <meta name="citation_author_institution" content="Cardiovascular Branch, National Heart Lung, and Blood Institute, National Institutes of Health, Bethesda, USA"/> <meta name="citation_author" content="Hwang, Paul M."/> <meta name="citation_author_institution" content="Cardiovascular Branch, National Heart Lung, and Blood Institute, National Institutes of Health, Bethesda, USA"/> <meta name="format-detection" content="telephone=no"/> <meta name="citation_cover_date" content="2005/05/01"/> <meta property="og:url" content="https://link.springer.com/article/10.1007/s11010-005-5905-8"/> <meta property="og:type" content="article"/> <meta property="og:site_name" content="SpringerLink"/> <meta property="og:title" content="Targeted disruption of p53 attenuates doxorubicin-induced cardiac toxicity in mice - Molecular and Cellular Biochemistry"/> <meta property="og:description" content="Use of the chemotherapeutic agent doxorubicin (Dox) is limited by dose-dependent cardiotoxic effects. The molecular mechanism underlying these toxicities are incompletely understood, but previous results have demonstrated that Dox induces p53 expression. Because p53 is an important regulator of the cell birth and death we hypothesized that targeted disruption of the p53 gene would attenuate Dox-induced cardiotoxicity. To test this, female 6–8 wk old C57BL wild-type (WT) or p53 knockout (p53 KO) mice were randomized to either saline or Dox 20 mg/kg via intraperitoneal injection. Animals were serially imaged with high-frequency (14 MHz) two-dimensional echocardiography. Measurements of left ventricle (LV) systolic function as assessed by fractional shortening (FS) demonstrated a decline in WT mice as early as 4 days after Dox injection and by 2 wk demonstrated a reduction of 31± 16% (P < 0.05) from the baseline. In contrast, in p53 KO mice, LV FS was unchanged over the 2 wk period following Dox injection. Apoptosis of cardiac myocytes as measured by the TUNEL and ligase reactions were significantly increased at 24 h after Dox treatment in WT mice but not in p53 KO mice. After Dox injection, levels of myocardial glutathione and Cu/Zn superoxide dismutase were preserved in p53 KO mice, but not in WT animals. These observations suggest that p53 mediated signals are likely to play a significant role in Dox-induced cardiac toxicity and that they may modulate Dox-induced oxidative stress."/> <meta property="og:image" content="https://media.springernature.com/full/springer-static/cover-hires/journal/11010"/> <meta name="format-detection" content="telephone=no"> <link rel="apple-touch-icon" sizes="180x180" href=/oscar-static/img/favicons/darwin/apple-touch-icon-92e819bf8a.png> <link rel="icon" type="image/png" sizes="192x192" href=/oscar-static/img/favicons/darwin/android-chrome-192x192-6f081ca7e5.png> <link rel="icon" type="image/png" sizes="32x32" href=/oscar-static/img/favicons/darwin/favicon-32x32-1435da3e82.png> <link rel="icon" type="image/png" sizes="16x16" href=/oscar-static/img/favicons/darwin/favicon-16x16-ed57f42bd2.png> <link rel="shortcut icon" data-test="shortcut-icon" href=/oscar-static/img/favicons/darwin/favicon-c6d59aafac.ico> <meta name="theme-color" content="#e6e6e6">   <link 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The molecular mechanism underlying these toxicities are incompletely understood, but previous results have demonstrated that Dox induces p53 expression. Because p53 is an important regulator of the cell birth and death we hypothesized that targeted disruption of the p53 gene would attenuate Dox-induced cardiotoxicity. To test this, female 6–8 wk old C57BL wild-type (WT) or p53 knockout (p53 KO) mice were randomized to either saline or Dox 20 mg/kg via intraperitoneal injection. Animals were serially imaged with high-frequency (14 MHz) two-dimensional echocardiography. Measurements of left ventricle (LV) systolic function as assessed by fractional shortening (FS) demonstrated a decline in WT mice as early as 4 days after Dox injection and by 2 wk demonstrated a reduction of 31± 16% (P < 0.05) from the baseline. In contrast, in p53 KO mice, LV FS was unchanged over the 2 wk period following Dox injection. Apoptosis of cardiac myocytes as measured by the TUNEL and ligase reactions were significantly increased at 24 h after Dox treatment in WT mice but not in p53 KO mice. After Dox injection, levels of myocardial glutathione and Cu/Zn superoxide dismutase were preserved in p53 KO mice, but not in WT animals. These observations suggest that p53 mediated signals are likely to play a significant role in Dox-induced cardiac toxicity and that they may modulate Dox-induced oxidative stress.","datePublished":"","dateModified":"","pageStart":"25","pageEnd":"32","sameAs":"https://doi.org/10.1007/s11010-005-5905-8","keywords":["cardiac toxicity","doxorubicin","p53","apoptosis","transgene","Biochemistry","general","Cardiology","Cancer Research","Medical Biochemistry"],"image":[],"isPartOf":{"name":"Molecular and Cellular Biochemistry","issn":["1573-4919","0300-8177"],"volumeNumber":"273","@type":["Periodical","PublicationVolume"]},"publisher":{"name":"Kluwer Academic Publishers","logo":{"url":"https://www.springernature.com/app-sn/public/images/logo-springernature.png","@type":"ImageObject"},"@type":"Organization"},"author":[{"name":"Yukitaka Shizukuda","affiliation":[{"name":"National Institutes of Health","address":{"name":"Cardiovascular Branch, National Heart Lung, and Blood Institute, National Institutes of Health, Bethesda, USA","@type":"PostalAddress"},"@type":"Organization"},{"name":"National Institutes of Health","address":{"name":"Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda","@type":"PostalAddress"},"@type":"Organization"}],"email":"shizukuy@nhlbi.nih.gov","@type":"Person"},{"name":"Satoaki Matoba","affiliation":[{"name":"National Institutes of Health","address":{"name":"Cardiovascular Branch, National Heart Lung, and Blood Institute, National Institutes of Health, Bethesda, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Omar Y. Mian","affiliation":[{"name":"National Institutes of Health","address":{"name":"Cardiovascular Branch, National Heart Lung, and Blood Institute, National Institutes of Health, Bethesda, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Tammy Nguyen","affiliation":[{"name":"National Institutes of Health","address":{"name":"Cardiovascular Branch, National Heart Lung, and Blood Institute, National Institutes of Health, Bethesda, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Paul M. Hwang","affiliation":[{"name":"National Institutes of Health","address":{"name":"Cardiovascular Branch, National Heart Lung, and Blood Institute, National Institutes of Health, Bethesda, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"}],"isAccessibleForFree":false,"hasPart":{"isAccessibleForFree":false,"cssSelector":".main-content","@type":"WebPageElement"},"@type":"ScholarlyArticle"},"@context":"https://schema.org","@type":"WebPage"}</script> </head> <body class="" >  <noscript> <iframe src="https://www.googletagmanager.com/ns.html?id=GTM-MRVXSHQ" height="0" width="0" style="display:none;visibility:hidden"></iframe> </noscript>   <noscript data-test="gtm-body"> <iframe src="https://www.googletagmanager.com/ns.html?id=GTM-MRVXSHQ" height="0" width="0" style="display:none;visibility:hidden"></iframe> </noscript>  <div class="u-visually-hidden" aria-hidden="true" data-test="darwin-icons"> <?xml version="1.0" encoding="UTF-8"?><!DOCTYPE svg PUBLIC "-//W3C//DTD SVG 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Mian</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Tammy-Nguyen-Aff1" data-author-popup="auth-Tammy-Nguyen-Aff1" data-author-search="Nguyen, Tammy">Tammy Nguyen</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 5 authors for this article" title="Show all 5 authors for this article">…</li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Paul_M_-Hwang-Aff1" data-author-popup="auth-Paul_M_-Hwang-Aff1" data-author-search="Hwang, Paul M.">Paul M. 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The molecular mechanism underlying these toxicities are incompletely understood, but previous results have demonstrated that Dox induces p53 expression. Because p53 is an important regulator of the cell birth and death we hypothesized that targeted disruption of the p53 gene would attenuate Dox-induced cardiotoxicity. To test this, female 6–8 wk old C57BL wild-type (WT) or p53 knockout (p53 KO) mice were randomized to either saline or Dox 20 mg/kg via intraperitoneal injection. Animals were serially imaged with high-frequency (14 MHz) two-dimensional echocardiography. Measurements of left ventricle (LV) systolic function as assessed by fractional shortening (FS) demonstrated a decline in WT mice as early as 4 days after Dox injection and by 2 wk demonstrated a reduction of 31± 16% (<i>P</i> < 0.05) from the baseline. In contrast, in p53 KO mice, LV FS was unchanged over the 2 wk period following Dox injection. Apoptosis of cardiac myocytes as measured by the TUNEL and ligase reactions were significantly increased at 24 h after Dox treatment in WT mice but not in p53 KO mice. After Dox injection, levels of myocardial glutathione and Cu/Zn superoxide dismutase were preserved in p53 KO mice, but not in WT animals. These observations suggest that p53 mediated signals are likely to play a significant role in Dox-induced cardiac toxicity and that they may modulate Dox-induced oxidative stress.</p></div></div></section> <div class="c-notes"> <p class="c-notes__text c-status-message--info"> <svg width="24" height="24" focusable="false" role="img" aria-hidden="true" class="c-status-message__icon"> <use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-info-filled-medium"></use> </svg> This is a preview of subscription content, <a id="test-login-banner-link" href="//wayf.springernature.com?redirect_uri=https%3A%2F%2Flink.springer.com%2Farticle%2F10.1007%2Fs11010-005-5905-8%3Ferror%3Dcookies_not_supported%26code%3D381d73a0-8bde-495f-908b-b487a2f23793" data-track="click" data-track-action="login" data-track-label="link" class="c-preview-message__link">log in via an institution</a> <svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon 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