WIPI1 is a conserved mediator of right ventricular failure
Identifieur interne : 000370 ( Pmc/Curation ); précédent : 000369; suivant : 000371WIPI1 is a conserved mediator of right ventricular failure
Auteurs : Christos Tzimas [États-Unis] ; Christoph D. Rau [États-Unis] ; Petra E. Buergisser [États-Unis] ; Gaston Jean-Louis [États-Unis] ; Katherine Lee [États-Unis] ; Jeffrey Chukwuneke [États-Unis] ; Wen Dun [États-Unis] ; Yibin Wang [États-Unis] ; Emily J. Tsai [États-Unis]Source :
- JCI Insight [ 2379-3708 ] ; ????.
Abstract
Right ventricular (RV) dysfunction is highly prevalent across cardiopulmonary diseases and independently predicts death in both heart failure (HF) and pulmonary hypertension (PH). Progression towards RV failure (RVF) can occur in spite of optimal medical treatment of HF or PH, highlighting current insufficient understanding of RVF molecular pathophysiology. To identify molecular mechanisms that may distinctly underlie RVF, we investigated the cardiac ventricular transcriptome of advanced-HF patients, with and without RVF. Using an integrated systems genomic and functional biology approach, we identified an RVF-specific gene module, for which
Url:
DOI: 10.1172/jci.insight.122929
PubMed: 31021818
PubMed Central: 6629151
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<front><div type="abstract" xml:lang="en"><p>Right ventricular (RV) dysfunction is highly prevalent across cardiopulmonary diseases and independently predicts death in both heart failure (HF) and pulmonary hypertension (PH). Progression towards RV failure (RVF) can occur in spite of optimal medical treatment of HF or PH, highlighting current insufficient understanding of RVF molecular pathophysiology. To identify molecular mechanisms that may distinctly underlie RVF, we investigated the cardiac ventricular transcriptome of advanced-HF patients, with and without RVF. Using an integrated systems genomic and functional biology approach, we identified an RVF-specific gene module, for which <italic>WIPI1</italic>
served as a hub and <italic>HSPB6</italic>
and <italic>MAP4</italic>
as drivers, and confirmed the ventricular specificity of <italic>Wipi1</italic>
, <italic>Hspb6</italic>
, and <italic>Map4</italic>
transcriptional changes in adult murine models of pressure overload–induced RV versus left ventricular failure. We uncovered a shift towards noncanonical autophagy in the failing RV that correlated with RV-specific <italic>Wipi1</italic>
upregulation. In vitro siRNA silencing of <italic>Wipi1</italic>
in neonatal rat ventricular myocytes limited noncanonical autophagy and blunted aldosterone-induced mitochondrial superoxide levels. Our findings suggest that <italic>Wipi1</italic>
regulates mitochondrial oxidative signaling and noncanonical autophagy in cardiac myocytes. Together with our human transcriptomic analysis and corroborating studies in an RVF mouse model, these data render <italic>Wipi1</italic>
a potential target for RV-directed HF therapy.</p>
</div>
</front>
</TEI>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">JCI Insight</journal-id>
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<article-id pub-id-type="doi">10.1172/jci.insight.122929</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
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<title-group><article-title><italic>WIPI1</italic>
is a conserved mediator of right ventricular failure</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Tzimas</surname>
<given-names>Christos</given-names>
</name>
<email>ct2836@cumc.columbia.edu</email>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0002-0782-207X</contrib-id>
<name><surname>Rau</surname>
<given-names>Christoph D.</given-names>
</name>
<email>chrau@ucla.edu</email>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Buergisser</surname>
<given-names>Petra E.</given-names>
</name>
<email>p.e.burgisser@gmail.com</email>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jean-Louis</surname>
<given-names>Gaston</given-names>
<suffix>Jr.</suffix>
</name>
<email>gj2279@cumc.columbia.edu</email>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lee</surname>
<given-names>Katherine</given-names>
</name>
<email>katherine.lee@downstate.edu</email>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chukwuneke</surname>
<given-names>Jeffrey</given-names>
</name>
<email>jeffrey.chukwuneke@gmail.com</email>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dun</surname>
<given-names>Wen</given-names>
</name>
<email>wd42@cumc.columbia.edu</email>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wang</surname>
<given-names>Yibin</given-names>
</name>
<email>yibinwang@mednet.ucla.edu</email>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Tsai</surname>
<given-names>Emily J.</given-names>
</name>
<email>et2509@cumc.columbia.edu</email>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Division of Cardiology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.</aff>
<aff id="A2"><label>2</label>
Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.</aff>
<aff id="A3"><label>3</label>
Institute of Human Nutrition, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.</aff>
<aff id="A4"><label>4</label>
Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA.</aff>
<author-notes><corresp>Address correspondence to: Emily J. Tsai, 630 W. 168th Street, P&S 8-510, New York, New York 10032, USA. Phone: 212.305.3409; Email: <email>emily.tsai@columbia.edu</email>
.</corresp>
<fn fn-type="COI-statement"><p><bold>Conflict of interest:</bold>
EJT and CT are co-inventors on a provisional patent application (62/836,315) that was filed on April 19, 2019 with the US Patent and Trademark Office. The patent relates to the pharmacologic treatment of right ventricular failure.</p>
</fn>
</author-notes>
<pub-date date-type="pub" publication-format="electronic" iso-8601-date="2019-06-06T09:00:00-0400"><day>6</day>
<month>6</month>
<year>2019</year>
</pub-date>
<pub-date date-type="collection" publication-format="electronic" iso-8601-date="2019-06-06T09:00:00-0400"><day>6</day>
<month>6</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>6</day>
<month>6</month>
<year>2019</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and
0 days and was based on the . </pmc-comment>
<volume>4</volume>
<issue>11</issue>
<elocation-id>e122929</elocation-id>
<history><date date-type="received"><day>5</day>
<month>7</month>
<year>2018</year>
</date>
<date date-type="accepted"><day>23</day>
<month>4</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© 2019 American Society for Clinical Investigation</copyright-statement>
<copyright-year>2019</copyright-year>
<copyright-holder>American Society for Clinical Investigation</copyright-holder>
</permissions>
<self-uri xlink:href="https://insight.jci.org/articles/view/122929">This article is available online at https://insight.jci.org/articles/view/122929</self-uri>
<abstract><p>Right ventricular (RV) dysfunction is highly prevalent across cardiopulmonary diseases and independently predicts death in both heart failure (HF) and pulmonary hypertension (PH). Progression towards RV failure (RVF) can occur in spite of optimal medical treatment of HF or PH, highlighting current insufficient understanding of RVF molecular pathophysiology. To identify molecular mechanisms that may distinctly underlie RVF, we investigated the cardiac ventricular transcriptome of advanced-HF patients, with and without RVF. Using an integrated systems genomic and functional biology approach, we identified an RVF-specific gene module, for which <italic>WIPI1</italic>
served as a hub and <italic>HSPB6</italic>
and <italic>MAP4</italic>
as drivers, and confirmed the ventricular specificity of <italic>Wipi1</italic>
, <italic>Hspb6</italic>
, and <italic>Map4</italic>
transcriptional changes in adult murine models of pressure overload–induced RV versus left ventricular failure. We uncovered a shift towards noncanonical autophagy in the failing RV that correlated with RV-specific <italic>Wipi1</italic>
upregulation. In vitro siRNA silencing of <italic>Wipi1</italic>
in neonatal rat ventricular myocytes limited noncanonical autophagy and blunted aldosterone-induced mitochondrial superoxide levels. Our findings suggest that <italic>Wipi1</italic>
regulates mitochondrial oxidative signaling and noncanonical autophagy in cardiac myocytes. Together with our human transcriptomic analysis and corroborating studies in an RVF mouse model, these data render <italic>Wipi1</italic>
a potential target for RV-directed HF therapy.</p>
</abstract>
<abstract abstract-type="toc"><p><italic>WIPI1</italic>
mediates mitochondrial oxidative stress signaling and noncanonical autophagy in right ventricular failure.</p>
</abstract>
<kwd-group kwd-group-type="specialties"><kwd>Cardiology</kwd>
</kwd-group>
<kwd-group kwd-group-type="keywords"><kwd>Cardiovascular disease</kwd>
<kwd>Heart failure</kwd>
<kwd>Molecular biology</kwd>
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<funding-group><award-group><funding-source>NHLBI</funding-source>
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<award-id>R01HL138527</award-id>
</award-group>
<award-group><funding-source><institution-wrap><institution>American Heart Association</institution>
<institution-id>https://doi.org/10.13039/100000968</institution-id>
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