Myeloid Cell Derived IL1β Contributes to Pulmonary Hypertension in HFpEF
BACKGROUND: Pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a common and highly morbid syndrome, but mechanisms driving PH-HFpEF are poorly understood. We sought to determine whether a well-accepted murine model of HFpEF also displays features of PH, and we sought to identify pathways that might drive early remodeling of the pulmonary vasculature in HFpEF.
METHODS: Eight-week-old male and female C57BL/6J mice received either Nγ-nitro-L-arginine methyl ester and high-fat diet or control water and diet for 2, 5, and 12 weeks. The db/db mice were studied as a second model of HFpEF. Early pathways regulating PH were identified by bulk and single-cell RNA sequencing. Findings were confirmed by immunostain in lungs of mice or lung slides from clinically performed autopsies of patients with PH-HFpEF. ELISA was used to verify IL-1β (interleukin-1 beta) in mouse lung, mouse plasma, and also human plasma from patients with PH-HFpEF obtained at the time of right heart catheterization. Clodronate liposomes and an anti-IL-1β antibody were utilized to deplete macrophages and IL-1β, respectively, to assess their impact on pulmonary vascular remodeling in HFpEF in mouse models.
RESULTS: Nγ-nitro-L-arginine methyl ester/high-fat diet-treated mice developed PH, small vessel muscularization, and right heart dysfunction. Inflammation-related gene ontologies were overrepresented in bulk RNA sequencing analysis of whole lungs, with an increase in CD68+ cells in both murine and human PH-HFpEF lungs. Cytokine profiling showed an increase in IL-1β in mouse and human plasma. Finally, clodronate liposome treatment in mice prevented PH in Nγ-nitro-L-arginine methyl ester/high-fat diet-treated mice, and IL-1β depletion also attenuated PH in Nγ-nitro-L-arginine methyl ester/high-fat diet-treated mice.
CONCLUSIONS: We report a novel model for the study of PH and right heart remodeling in HFpEF, and we identify myeloid cell-derived IL-1β as an important contributor to PH in HFpEF.
| Errataetall: |
CommentIn: Circ Res. 2023 Nov 10;133(11):899-901. - PMID 37943948 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:133 |
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| Enthalten in: |
Circulation research - 133(2023), 11 vom: 10. Nov., Seite 885-898 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Agrawal, Vineet [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.11.2023 Date Revised 14.03.2024 published: Print-Electronic CommentIn: Circ Res. 2023 Nov 10;133(11):899-901. - PMID 37943948 Citation Status MEDLINE |
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| doi: |
10.1161/CIRCRESAHA.123.323119 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Myeloid Cell Derived IL1β Contributes to Pulmonary Hypertension in HFpEF |
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| 500 | |a Date Revised 14.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Circ Res. 2023 Nov 10;133(11):899-901. - PMID 37943948 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: Pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a common and highly morbid syndrome, but mechanisms driving PH-HFpEF are poorly understood. We sought to determine whether a well-accepted murine model of HFpEF also displays features of PH, and we sought to identify pathways that might drive early remodeling of the pulmonary vasculature in HFpEF | ||
| 520 | |a METHODS: Eight-week-old male and female C57BL/6J mice received either Nγ-nitro-L-arginine methyl ester and high-fat diet or control water and diet for 2, 5, and 12 weeks. The db/db mice were studied as a second model of HFpEF. Early pathways regulating PH were identified by bulk and single-cell RNA sequencing. Findings were confirmed by immunostain in lungs of mice or lung slides from clinically performed autopsies of patients with PH-HFpEF. ELISA was used to verify IL-1β (interleukin-1 beta) in mouse lung, mouse plasma, and also human plasma from patients with PH-HFpEF obtained at the time of right heart catheterization. Clodronate liposomes and an anti-IL-1β antibody were utilized to deplete macrophages and IL-1β, respectively, to assess their impact on pulmonary vascular remodeling in HFpEF in mouse models | ||
| 520 | |a RESULTS: Nγ-nitro-L-arginine methyl ester/high-fat diet-treated mice developed PH, small vessel muscularization, and right heart dysfunction. Inflammation-related gene ontologies were overrepresented in bulk RNA sequencing analysis of whole lungs, with an increase in CD68+ cells in both murine and human PH-HFpEF lungs. Cytokine profiling showed an increase in IL-1β in mouse and human plasma. Finally, clodronate liposome treatment in mice prevented PH in Nγ-nitro-L-arginine methyl ester/high-fat diet-treated mice, and IL-1β depletion also attenuated PH in Nγ-nitro-L-arginine methyl ester/high-fat diet-treated mice | ||
| 520 | |a CONCLUSIONS: We report a novel model for the study of PH and right heart remodeling in HFpEF, and we identify myeloid cell-derived IL-1β as an important contributor to PH in HFpEF | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a cytokines | |
| 650 | 4 | |a heart failure | |
| 650 | 4 | |a hypertension, pulmonary | |
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| 700 | 1 | |a Kropski, Jonathan A |e verfasserin |4 aut | |
| 700 | 1 | |a Gokey, Jason J |e verfasserin |4 aut | |
| 700 | 1 | |a Kobeck, Elizabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Murphy, Matthew B |e verfasserin |4 aut | |
| 700 | 1 | |a Murray, Katherine T |e verfasserin |4 aut | |
| 700 | 1 | |a Fortune, Niki L |e verfasserin |4 aut | |
| 700 | 1 | |a Moore, Christy S |e verfasserin |4 aut | |
| 700 | 1 | |a Meoli, David F |e verfasserin |4 aut | |
| 700 | 1 | |a Monahan, Ken |e verfasserin |4 aut | |
| 700 | 1 | |a Ru Su, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Blackwell, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Gupta, Deepak K |e verfasserin |4 aut | |
| 700 | 1 | |a Talati, Megha H |e verfasserin |4 aut | |
| 700 | 1 | |a Gladson, Santhi |e verfasserin |4 aut | |
| 700 | 1 | |a Carrier, Erica J |e verfasserin |4 aut | |
| 700 | 1 | |a West, James D |e verfasserin |4 aut | |
| 700 | 1 | |a Hemnes, Anna R |e verfasserin |4 aut | |
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