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Precursor proadrenomedullin influences cardiomyocyte survival and local inflammation related to myocardial infarction

Svenja Hinrichs, Katharina Scherschel, Saskia Krüger, Johannes Tobias Neumann, Michael Schwarzl, Isabell Yan, Svenja Warnke, Francisco M. Ojeda, Tanja Zeller, Mahir Karakas, Till Keller, Christian Meyer, Stefan Blankenberg, Dirk Westermann, and Diana Lindner
PNAS September 11, 2018 115 (37) E8727-E8736; published ahead of print August 30, 2018 https://doi.org/10.1073/pnas.1721635115
Svenja Hinrichs
aClinic for General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany;bPartner Site Hamburg/Kiel/Lübeck, German Center for Cardiovascular Research, 20246 Hamburg, Germany;
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Katharina Scherschel
bPartner Site Hamburg/Kiel/Lübeck, German Center for Cardiovascular Research, 20246 Hamburg, Germany;cClinic for Cardiology–Electrophysiology, University Heart Center Hamburg, 20246 Hamburg, Germany;
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Saskia Krüger
aClinic for General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany;bPartner Site Hamburg/Kiel/Lübeck, German Center for Cardiovascular Research, 20246 Hamburg, Germany;
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  • ORCID record for Saskia Krüger
Johannes Tobias Neumann
aClinic for General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany;bPartner Site Hamburg/Kiel/Lübeck, German Center for Cardiovascular Research, 20246 Hamburg, Germany;
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Michael Schwarzl
aClinic for General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany;bPartner Site Hamburg/Kiel/Lübeck, German Center for Cardiovascular Research, 20246 Hamburg, Germany;
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Isabell Yan
aClinic for General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany;bPartner Site Hamburg/Kiel/Lübeck, German Center for Cardiovascular Research, 20246 Hamburg, Germany;
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Svenja Warnke
aClinic for General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany;
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Francisco M. Ojeda
aClinic for General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany;bPartner Site Hamburg/Kiel/Lübeck, German Center for Cardiovascular Research, 20246 Hamburg, Germany;
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Tanja Zeller
aClinic for General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany;bPartner Site Hamburg/Kiel/Lübeck, German Center for Cardiovascular Research, 20246 Hamburg, Germany;
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Mahir Karakas
aClinic for General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany;bPartner Site Hamburg/Kiel/Lübeck, German Center for Cardiovascular Research, 20246 Hamburg, Germany;
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Till Keller
dDivision of Cardiology, Department of Medicine III, Goethe University Frankfurt, 60598 Frankfurt, Germany;ePartner Site Frankfurt, German Center for Cardiovascular Research, 60589 Frankfurt, Germany
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Christian Meyer
bPartner Site Hamburg/Kiel/Lübeck, German Center for Cardiovascular Research, 20246 Hamburg, Germany;cClinic for Cardiology–Electrophysiology, University Heart Center Hamburg, 20246 Hamburg, Germany;
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Stefan Blankenberg
aClinic for General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany;bPartner Site Hamburg/Kiel/Lübeck, German Center for Cardiovascular Research, 20246 Hamburg, Germany;
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Dirk Westermann
aClinic for General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany;bPartner Site Hamburg/Kiel/Lübeck, German Center for Cardiovascular Research, 20246 Hamburg, Germany;
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Diana Lindner
aClinic for General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany;bPartner Site Hamburg/Kiel/Lübeck, German Center for Cardiovascular Research, 20246 Hamburg, Germany;
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  • For correspondence: d.lindner@uke.de
  1. Edited by Jonathan G. Seidman, Harvard Medical School, Boston, MA, and approved August 7, 2018 (received for review December 14, 2017)

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Significance

Myocardial infarction (MI) is one of the leading causes of death worldwide and is characterized by apoptosis and inflammation. While increased adrenomedullin (ADM) levels after MI are associated with disease severity, ADM infusion leads to antiapoptotic effects, suggesting a self-protective mechanism. ADM is cleaved from a full‐length precursor protein (ProADM), a putatively inactive prohormone. Our data show that ProADM is biologically active by reducing apoptosis to a similar extent as ADM. In contrast to ADM, ProADM has proinflammatory effects on cardiac fibroblasts but antiinflammatory effects on activated leukocytes. We assume that ProADM induces local inflammation but attenuates exaggerated inflammation. Our data suggest that both proteins are beneficial during MI by regulating inflammation and reducing apoptosis of cardiomyocytes.

Abstract

Increased adrenomedullin (ADM) levels are associated with various cardiac diseases such as myocardial infarction (MI). ADM is cleaved off from the full-length precursor protein proadrenomedullin (ProADM) during its posttranslational processing. To date, no biological effect of ProADM is reported, while ADM infusion leads to antiapoptotic effects and improved cardiac function. Using an MI mouse model, we found an induction of ProADM gene as well as protein expression during the early phase of MI. This was accompanied by apoptosis and increasing inflammation, which substantially influence the post-MI remodeling processes. Simulating ischemia in vitro, we demonstrate that ProADM expression was increased in cardiomyocytes and cardiac fibroblasts. Subsequently, we treated ischemic cardiomyocytes with either ProADM or ADM and found that both proteins increased survival. This effect was diminishable by blocking the ADM1 receptor. To investigate whether ProADM and ADM play a role in the regulation of cardiac inflammation, we analyzed chemokine expression after treatment of cells with both proteins. While ProADM induced an expression of proinflammatory cytokines, thus promoting inflammation, ADM reduced chemokine expression. On leukocytes, both proteins repressed chemokine expression, revealing antiinflammatory effects. However, ProADM but not ADM dampened concurrent activation of leukocytes. Our data show that the full-length precursor ProADM is biologically active by reducing apoptosis to a similar extent as ADM. We further assume that ProADM induces local inflammation in affected cardiac tissue but attenuates exaggerated inflammation, whereas ADM has low impact. Our data suggest that both proteins are beneficial during MI by influencing apoptosis and inflammation.

  • adrenomedullin
  • proadrenomedullin
  • myocardial infarction
  • ischemia
  • cardioprotection

Footnotes

  • ↵1D.W. and D.L. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. Email: d.lindner{at}uke.de.
  • Author contributions: S.H., M.S., T.Z., M.K., T.K., C.M., S.B., D.W., and D.L. designed research; S.H., K.S., S.K., M.S., I.Y., S.W., and D.L. performed research; S.H., K.S., S.K., J.T.N., F.M.O., D.W., and D.L. analyzed data; and S.H., S.K., D.W., and D.L. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1721635115/-/DCSupplemental.

Published under the PNAS license.

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Precursor proadrenomedullin influences cardiomyocyte survival and local inflammation related to myocardial infarction
Svenja Hinrichs, Katharina Scherschel, Saskia Krüger, Johannes Tobias Neumann, Michael Schwarzl, Isabell Yan, Svenja Warnke, Francisco M. Ojeda, Tanja Zeller, Mahir Karakas, Till Keller, Christian Meyer, Stefan Blankenberg, Dirk Westermann, Diana Lindner
Proceedings of the National Academy of Sciences Sep 2018, 115 (37) E8727-E8736; DOI: 10.1073/pnas.1721635115

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Precursor proadrenomedullin influences cardiomyocyte survival and local inflammation related to myocardial infarction
Svenja Hinrichs, Katharina Scherschel, Saskia Krüger, Johannes Tobias Neumann, Michael Schwarzl, Isabell Yan, Svenja Warnke, Francisco M. Ojeda, Tanja Zeller, Mahir Karakas, Till Keller, Christian Meyer, Stefan Blankenberg, Dirk Westermann, Diana Lindner
Proceedings of the National Academy of Sciences Sep 2018, 115 (37) E8727-E8736; DOI: 10.1073/pnas.1721635115
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