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HMGB1‐Promoted Neutrophil Extracellular Traps Contribute to Cardiac Diastolic Dysfunction in Mice

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) remains an increasing public health problem with substantial morbidity and mortality but with few effective treatments. A novel inflammatory mechanism has been proposed, but the inflammatory signals promoting the development of HFpEF...

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Autores principales: Zhang, Xin‐Lin, Wang, Ting‐Yu, Chen, Zheng, Wang, Hong‐Wei, Yin, Yong, Wang, Lian, Wang, Yong, Xu, Biao, Xu, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9245819/
https://www.ncbi.nlm.nih.gov/pubmed/35156391
http://dx.doi.org/10.1161/JAHA.121.023800
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author Zhang, Xin‐Lin
Wang, Ting‐Yu
Chen, Zheng
Wang, Hong‐Wei
Yin, Yong
Wang, Lian
Wang, Yong
Xu, Biao
Xu, Wei
author_facet Zhang, Xin‐Lin
Wang, Ting‐Yu
Chen, Zheng
Wang, Hong‐Wei
Yin, Yong
Wang, Lian
Wang, Yong
Xu, Biao
Xu, Wei
author_sort Zhang, Xin‐Lin
collection PubMed
description BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) remains an increasing public health problem with substantial morbidity and mortality but with few effective treatments. A novel inflammatory mechanism has been proposed, but the inflammatory signals promoting the development of HFpEF remain greatly unknown. METHODS AND RESULTS: Serum of patients with HFpEF was collected for measurement of circulating neutrophils and markers of neutrophil extracellular traps (NETs). To induce HFpEF phenotype, male C57BL/6 mice underwent uninephrectomy, received a continuous infusion of d‐aldosterone for 4 weeks, and maintained on 1.0% sodium chloride drinking water. Heart tissues were harvested, immune cell types determined by flow cytometry, NETs formation by immunofluorescence, and western blotting. Differentiated neutrophils were cultured to investigate the effect of HMGB1 (high mobility group protein B1) and SGLT2 (sodium‐glucose cotransporter‐2) inhibitor on NETs formation in vitro. Circulating neutrophils and NETs markers are elevated in patients with HFpEF, as are cardiac neutrophils and NETs formation in HFpEF mice. NETs inhibition with deoxyribonuclease 1 in experimental HFpEF mice reduces heart macrophages infiltration and inflammation and ameliorates cardiac fibrosis and diastolic function. Damage‐associated molecular pattern HMGB1 expression is elevated in cardiac tissue of HFpEF mice, and HMGB1 inhibition reduces heart neutrophil infiltration and NETs formation and ameliorates diastolic function. Lastly, SGLT2 inhibitor empagliflozin down‐regulates heart HMGB1 expression, attenuates NETs formation and cardiac fibrosis, and improves diastolic function in HFpEF mice. CONCLUSIONS: NETs contribute to the pathogenesis of HFpEF, which can be ameliorated by HMGB1 inhibition and SGLT2 inhibitors. Thus, HMGB1 and NETs may represent novel therapeutic targets for the treatment of HFpEF.
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spelling pubmed-92458192022-07-01 HMGB1‐Promoted Neutrophil Extracellular Traps Contribute to Cardiac Diastolic Dysfunction in Mice Zhang, Xin‐Lin Wang, Ting‐Yu Chen, Zheng Wang, Hong‐Wei Yin, Yong Wang, Lian Wang, Yong Xu, Biao Xu, Wei J Am Heart Assoc Original Research BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) remains an increasing public health problem with substantial morbidity and mortality but with few effective treatments. A novel inflammatory mechanism has been proposed, but the inflammatory signals promoting the development of HFpEF remain greatly unknown. METHODS AND RESULTS: Serum of patients with HFpEF was collected for measurement of circulating neutrophils and markers of neutrophil extracellular traps (NETs). To induce HFpEF phenotype, male C57BL/6 mice underwent uninephrectomy, received a continuous infusion of d‐aldosterone for 4 weeks, and maintained on 1.0% sodium chloride drinking water. Heart tissues were harvested, immune cell types determined by flow cytometry, NETs formation by immunofluorescence, and western blotting. Differentiated neutrophils were cultured to investigate the effect of HMGB1 (high mobility group protein B1) and SGLT2 (sodium‐glucose cotransporter‐2) inhibitor on NETs formation in vitro. Circulating neutrophils and NETs markers are elevated in patients with HFpEF, as are cardiac neutrophils and NETs formation in HFpEF mice. NETs inhibition with deoxyribonuclease 1 in experimental HFpEF mice reduces heart macrophages infiltration and inflammation and ameliorates cardiac fibrosis and diastolic function. Damage‐associated molecular pattern HMGB1 expression is elevated in cardiac tissue of HFpEF mice, and HMGB1 inhibition reduces heart neutrophil infiltration and NETs formation and ameliorates diastolic function. Lastly, SGLT2 inhibitor empagliflozin down‐regulates heart HMGB1 expression, attenuates NETs formation and cardiac fibrosis, and improves diastolic function in HFpEF mice. CONCLUSIONS: NETs contribute to the pathogenesis of HFpEF, which can be ameliorated by HMGB1 inhibition and SGLT2 inhibitors. Thus, HMGB1 and NETs may represent novel therapeutic targets for the treatment of HFpEF. John Wiley and Sons Inc. 2022-02-12 /pmc/articles/PMC9245819/ /pubmed/35156391 http://dx.doi.org/10.1161/JAHA.121.023800 Text en © 2022 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Research
Zhang, Xin‐Lin
Wang, Ting‐Yu
Chen, Zheng
Wang, Hong‐Wei
Yin, Yong
Wang, Lian
Wang, Yong
Xu, Biao
Xu, Wei
HMGB1‐Promoted Neutrophil Extracellular Traps Contribute to Cardiac Diastolic Dysfunction in Mice
title HMGB1‐Promoted Neutrophil Extracellular Traps Contribute to Cardiac Diastolic Dysfunction in Mice
title_full HMGB1‐Promoted Neutrophil Extracellular Traps Contribute to Cardiac Diastolic Dysfunction in Mice
title_fullStr HMGB1‐Promoted Neutrophil Extracellular Traps Contribute to Cardiac Diastolic Dysfunction in Mice
title_full_unstemmed HMGB1‐Promoted Neutrophil Extracellular Traps Contribute to Cardiac Diastolic Dysfunction in Mice
title_short HMGB1‐Promoted Neutrophil Extracellular Traps Contribute to Cardiac Diastolic Dysfunction in Mice
title_sort hmgb1‐promoted neutrophil extracellular traps contribute to cardiac diastolic dysfunction in mice
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9245819/
https://www.ncbi.nlm.nih.gov/pubmed/35156391
http://dx.doi.org/10.1161/JAHA.121.023800
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