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B-type natriuretic peptide is upregulated by c-Jun N-terminal kinase and contributes to septic hypotension

B-type natriuretic peptide (BNP) is secreted by ventricular cardiomyocytes in response to various types of cardiac stress and has been used as a heart failure marker. In septic patients, increased BNP suggests poor prognosis; however, no causal link has been established. Among various effects, BNP d...

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Autores principales: Hoffman, Matthew, Kyriazis, Ioannis D., Dimitriou, Alexandra, Mishra, Santosh K., Koch, Walter J., Drosatos, Konstantinos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205432/
https://www.ncbi.nlm.nih.gov/pubmed/32324169
http://dx.doi.org/10.1172/jci.insight.133675
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author Hoffman, Matthew
Kyriazis, Ioannis D.
Dimitriou, Alexandra
Mishra, Santosh K.
Koch, Walter J.
Drosatos, Konstantinos
author_facet Hoffman, Matthew
Kyriazis, Ioannis D.
Dimitriou, Alexandra
Mishra, Santosh K.
Koch, Walter J.
Drosatos, Konstantinos
author_sort Hoffman, Matthew
collection PubMed
description B-type natriuretic peptide (BNP) is secreted by ventricular cardiomyocytes in response to various types of cardiac stress and has been used as a heart failure marker. In septic patients, increased BNP suggests poor prognosis; however, no causal link has been established. Among various effects, BNP decreases systemic vascular resistance and increases natriuresis that leads to lower blood pressure. We previously observed that JNK inhibition corrects cardiac dysfunction and suppresses cardiac BNP mRNA in endotoxemia. In this study, we investigated the transcriptional mechanism that regulates BNP expression and the involvement of plasma BNP in causing septic hypotension. Our in vitro and in vivo findings confirmed that activation of JNK signaling increases BNP expression in sepsis via direct binding of c-Jun in activating protein–1 (AP-1) regulatory elements of the Nppb promoter. Accordingly, genetic ablation of BNP, as well as treatment with a potentially novel neutralizing anti-BNP monoclonal antibody (19B3) or suppression of its expression via administration of JNK inhibitor SP600125 improved cardiac output, stabilized blood pressure, and improved survival in mice with polymicrobial sepsis. Therefore, inhibition of JNK signaling or BNP in sepsis appears to stabilize blood pressure and improve survival.
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spelling pubmed-72054322020-05-12 B-type natriuretic peptide is upregulated by c-Jun N-terminal kinase and contributes to septic hypotension Hoffman, Matthew Kyriazis, Ioannis D. Dimitriou, Alexandra Mishra, Santosh K. Koch, Walter J. Drosatos, Konstantinos JCI Insight Research Article B-type natriuretic peptide (BNP) is secreted by ventricular cardiomyocytes in response to various types of cardiac stress and has been used as a heart failure marker. In septic patients, increased BNP suggests poor prognosis; however, no causal link has been established. Among various effects, BNP decreases systemic vascular resistance and increases natriuresis that leads to lower blood pressure. We previously observed that JNK inhibition corrects cardiac dysfunction and suppresses cardiac BNP mRNA in endotoxemia. In this study, we investigated the transcriptional mechanism that regulates BNP expression and the involvement of plasma BNP in causing septic hypotension. Our in vitro and in vivo findings confirmed that activation of JNK signaling increases BNP expression in sepsis via direct binding of c-Jun in activating protein–1 (AP-1) regulatory elements of the Nppb promoter. Accordingly, genetic ablation of BNP, as well as treatment with a potentially novel neutralizing anti-BNP monoclonal antibody (19B3) or suppression of its expression via administration of JNK inhibitor SP600125 improved cardiac output, stabilized blood pressure, and improved survival in mice with polymicrobial sepsis. Therefore, inhibition of JNK signaling or BNP in sepsis appears to stabilize blood pressure and improve survival. American Society for Clinical Investigation 2020-04-23 /pmc/articles/PMC7205432/ /pubmed/32324169 http://dx.doi.org/10.1172/jci.insight.133675 Text en © 2020 Hoffman et al. http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research Article
Hoffman, Matthew
Kyriazis, Ioannis D.
Dimitriou, Alexandra
Mishra, Santosh K.
Koch, Walter J.
Drosatos, Konstantinos
B-type natriuretic peptide is upregulated by c-Jun N-terminal kinase and contributes to septic hypotension
title B-type natriuretic peptide is upregulated by c-Jun N-terminal kinase and contributes to septic hypotension
title_full B-type natriuretic peptide is upregulated by c-Jun N-terminal kinase and contributes to septic hypotension
title_fullStr B-type natriuretic peptide is upregulated by c-Jun N-terminal kinase and contributes to septic hypotension
title_full_unstemmed B-type natriuretic peptide is upregulated by c-Jun N-terminal kinase and contributes to septic hypotension
title_short B-type natriuretic peptide is upregulated by c-Jun N-terminal kinase and contributes to septic hypotension
title_sort b-type natriuretic peptide is upregulated by c-jun n-terminal kinase and contributes to septic hypotension
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205432/
https://www.ncbi.nlm.nih.gov/pubmed/32324169
http://dx.doi.org/10.1172/jci.insight.133675
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