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. / Hinrichs, Svenja; Scherschel, Katharina; Krüger, Saskia; Neumann, Johannes Tobias; Schwarzl, Michael; Yan, Isabell; Warnke, Svenja; Ojeda, Francisco M; Zeller, Tanja; Karakas, Mahir; Keller, Till; Meyer, Christian; Blankenberg, Stefan; Westermann, Dirk; Lindner, Diana.
In: P NATL ACAD SCI USA, Vol. 115, No. 37, 11.09.2018, p. E8727-E8736.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Precursor proadrenomedullin influences cardiomyocyte survival and local inflammation related to myocardial infarction
AU - Hinrichs, Svenja
AU - Scherschel, Katharina
AU - Krüger, Saskia
AU - Neumann, Johannes Tobias
AU - Schwarzl, Michael
AU - Yan, Isabell
AU - Warnke, Svenja
AU - Ojeda, Francisco M
AU - Zeller, Tanja
AU - Karakas, Mahir
AU - Keller, Till
AU - Meyer, Christian
AU - Blankenberg, Stefan
AU - Westermann, Dirk
AU - Lindner, Diana
PY - 2018/9/11
Y1 - 2018/9/11
N2 - 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.
AB - 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.
KW - Adrenomedullin/genetics
KW - Aged
KW - Animals
KW - Apoptosis/drug effects
KW - Cells, Cultured
KW - Cytokines/metabolism
KW - Female
KW - Gene Expression/genetics
KW - Humans
KW - Inflammation/genetics
KW - Inflammation Mediators/metabolism
KW - Male
KW - Mice, Inbred C57BL
KW - Middle Aged
KW - Myocardial Infarction/genetics
KW - Myocytes, Cardiac/drug effects
KW - Protein Precursors/genetics
U2 - 10.1073/pnas.1721635115
DO - 10.1073/pnas.1721635115
M3 - SCORING: Journal article
C2 - 30166452
VL - 115
SP - E8727-E8736
JO - P NATL ACAD SCI USA
JF - P NATL ACAD SCI USA
SN - 0027-8424
IS - 37
ER -