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

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 -