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

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.

SUBMITTER: Hinrichs S

PROVIDER: S-EPMC6140510 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Hinrichs Svenja S Scherschel Katharina K Krüger Saskia S Neumann Johannes Tobias JT Schwarzl Michael M Yan Isabell I Warnke Svenja S Ojeda Francisco M FM Zeller Tanja T Karakas Mahir M Keller Till T Meyer Christian C Blankenberg Stefan S Westermann Dirk D Lindner Diana D

Proceedings of the National Academy of Sciences of the United States of America 20180830 37

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. ...[more]

PMID: 30166452

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

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

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