Nicotinamide riboside promotes autolysosome clearance in preventing doxorubicin-induced cardiotoxicity
Identifieur interne : 000389 ( Pmc/Curation ); précédent : 000388; suivant : 000390Nicotinamide riboside promotes autolysosome clearance in preventing doxorubicin-induced cardiotoxicity
Auteurs : Dong Zheng [République populaire de Chine, Canada] ; Yi Zhang [République populaire de Chine] ; Ming Zheng [République populaire de Chine] ; Ting Cao [République populaire de Chine] ; Grace Wang [Canada] ; Lulu Zhang [République populaire de Chine] ; Rui Ni [Canada] ; Joseph Brockman [Canada] ; Huiting Zhong [République populaire de Chine] ; Guo-Chang Fan [États-Unis] ; Tianqing Peng [République populaire de Chine, Canada]Source :
- Clinical science (London, England : 1979) [ 0143-5221 ] ; 2019.
Abstract
Doxorubicin (DOX) is widely used as a first-line chemotherapeutic drug for various malignancies. However, DOX causes severe cardiotoxicity, which limits its clinical uses. Oxidative stress is one of major contributors to DOX-induced cardiotoxicity. While autophagic flux serves as an important defense mechanism against oxidative stress in cardiomyocytes, recent studies have demonstrated that DOX induces the blockage of autophagic flux, which contributes to DOX cardiotoxicity. The present study investigated whether nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD)+, prevents DOX cardiotoxicity by improving autophagic flux. We report that administration of NR elevated NAD+ levels, and reduced cardiac injury and myocardial dysfunction in DOX-injected mice. These protective effects of NR were recapitulated in cultured cardiomyocytes upon DOX treatment. Mechanistically, NR prevented the blockage of autophagic flux, accumulation of autolysosomes, and oxidative stress in DOX-treated cardiomyocytes, the effects of which were associated with restoration of lysosomal acidification. Furthermore, inhibition of lysosomal acidification or SIRT1 abrogated these protective effects of NR during DOX-induced cardiotoxicity. Collectively, our study shows that NR enhances autolysosome clearance via the NAD+/SIRT1 signaling, thereby preventing DOX-triggered cardiotoxicity.
Url:
DOI: 10.1042/CS20181022
PubMed: 31266854
PubMed Central: 6705112
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<front><div type="abstract" xml:lang="en"><p id="P4">Doxorubicin (DOX) is widely used as a first-line chemotherapeutic drug for various malignancies. However, DOX causes severe cardiotoxicity, which limits its clinical uses. Oxidative stress is one of major contributors to DOX-induced cardiotoxicity. While autophagic flux serves as an important defense mechanism against oxidative stress in cardiomyocytes, recent studies have demonstrated that DOX induces the blockage of autophagic flux, which contributes to DOX cardiotoxicity. The present study investigated whether nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD)<sup>+</sup>
, prevents DOX cardiotoxicity by improving autophagic flux. We report that administration of NR elevated NAD<sup>+</sup>
levels, and reduced cardiac injury and myocardial dysfunction in DOX-injected mice. These protective effects of NR were recapitulated in cultured cardiomyocytes upon DOX treatment. Mechanistically, NR prevented the blockage of autophagic flux, accumulation of autolysosomes, and oxidative stress in DOX-treated cardiomyocytes, the effects of which were associated with restoration of lysosomal acidification. Furthermore, inhibition of lysosomal acidification or SIRT1 abrogated these protective effects of NR during DOX-induced cardiotoxicity. Collectively, our study shows that NR enhances autolysosome clearance via the NAD<sup>+</sup>
/SIRT1 signaling, thereby preventing DOX-triggered cardiotoxicity.</p>
</div>
</front>
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<front><journal-meta><journal-id journal-id-type="nlm-journal-id">7905731</journal-id>
<journal-id journal-id-type="pubmed-jr-id">3071</journal-id>
<journal-id journal-id-type="nlm-ta">Clin Sci (Lond)</journal-id>
<journal-id journal-id-type="iso-abbrev">Clin. Sci.</journal-id>
<journal-title-group><journal-title>Clinical science (London, England : 1979)</journal-title>
</journal-title-group>
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<issn pub-type="epub">1470-8736</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31266854</article-id>
<article-id pub-id-type="pmc">6705112</article-id>
<article-id pub-id-type="doi">10.1042/CS20181022</article-id>
<article-id pub-id-type="manuscript">NIHMS1046618</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Nicotinamide riboside promotes autolysosome clearance in preventing doxorubicin-induced cardiotoxicity</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Zheng</surname>
<given-names>Dong</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
<xref rid="FN3" ref-type="author-notes">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhang</surname>
<given-names>Yi</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref rid="FN3" ref-type="author-notes">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zheng</surname>
<given-names>Ming</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cao</surname>
<given-names>Ting</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wang</surname>
<given-names>Grace</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhang</surname>
<given-names>Lulu</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ni</surname>
<given-names>Rui</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Brockman</surname>
<given-names>Joseph</given-names>
</name>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhong</surname>
<given-names>Huiting</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fan</surname>
<given-names>Guo-Chang</given-names>
</name>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Peng</surname>
<given-names>Tianqing</given-names>
</name>
<contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-5199-9016</contrib-id>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China;</aff>
<aff id="A2"><label>2</label>
Critical Illness Research, Lawson Health Research Institute, London Health Sciences Centre, VRL 6th Floor, A6-140, 800 Commissioners Road, London, ON, Canada N6A 4S2;</aff>
<aff id="A3"><label>3</label>
Departments of Medicine and Pathology and Laboratory Medicine, Western University, London, ON, Canada N6A 4S2;</aff>
<aff id="A4"><label>4</label>
Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON, Canada M5S 1A8;</aff>
<aff id="A5"><label>5</label>
Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, U.S.A.</aff>
<author-notes><fn fn-type="con" id="FN1"><p id="P1">Author Contribution</p>
<p id="P2">D.Z., Y.Z., M.Z., H.Z., G.W., L.Z., R.N., J.B., and T.C. performed experiments. D.Z., J.B., and T.P. analyzed data. G.W., G-C.F., and T.P. discussed data and wrote manuscript. D.Z. and T.P. designed studies and experiments.</p>
</fn>
<fn fn-type="equal" id="FN3"><label>*</label>
<p id="P3">These authors equally contribute to this work.</p>
</fn>
<corresp id="CR1"><bold>Correspondence:</bold>
Tianqing Peng (<email>tqpeng@suda.edu.cn</email>
)</corresp>
<fn fn-type="COI-statement" id="FN4"><p id="P49">Competing Interests</p>
<p id="P50">The authors declare that there are no competing interests associated with the manuscript.</p>
</fn>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>17</day>
<month>8</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="epub"><day>15</day>
<month>7</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="ppub"><day>15</day>
<month>7</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>22</day>
<month>8</month>
<year>2019</year>
</pub-date>
<volume>133</volume>
<issue>13</issue>
<fpage>1505</fpage>
<lpage>1521</lpage>
<pmc-comment>elocation-id from pubmed: 10.1042/CS20181022</pmc-comment>
<abstract id="ABS1"><p id="P4">Doxorubicin (DOX) is widely used as a first-line chemotherapeutic drug for various malignancies. However, DOX causes severe cardiotoxicity, which limits its clinical uses. Oxidative stress is one of major contributors to DOX-induced cardiotoxicity. While autophagic flux serves as an important defense mechanism against oxidative stress in cardiomyocytes, recent studies have demonstrated that DOX induces the blockage of autophagic flux, which contributes to DOX cardiotoxicity. The present study investigated whether nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD)<sup>+</sup>
, prevents DOX cardiotoxicity by improving autophagic flux. We report that administration of NR elevated NAD<sup>+</sup>
levels, and reduced cardiac injury and myocardial dysfunction in DOX-injected mice. These protective effects of NR were recapitulated in cultured cardiomyocytes upon DOX treatment. Mechanistically, NR prevented the blockage of autophagic flux, accumulation of autolysosomes, and oxidative stress in DOX-treated cardiomyocytes, the effects of which were associated with restoration of lysosomal acidification. Furthermore, inhibition of lysosomal acidification or SIRT1 abrogated these protective effects of NR during DOX-induced cardiotoxicity. Collectively, our study shows that NR enhances autolysosome clearance via the NAD<sup>+</sup>
/SIRT1 signaling, thereby preventing DOX-triggered cardiotoxicity.</p>
</abstract>
</article-meta>
</front>
</pmc>
</record>
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