Glycocalyx Disruption Triggers Human Monocyte Activation in Acute Heart Failure Syndromes.

Autor: Grushko OG; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.; University of Michigan Frankel Cardiovascular Center, 1500 East Medical Center Drive, SPC 5853, Ann Arbor, MI, 48109-5853, USA., Cho S; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.; University of Michigan Frankel Cardiovascular Center, 1500 East Medical Center Drive, SPC 5853, Ann Arbor, MI, 48109-5853, USA., Tate AM; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.; University of Michigan Frankel Cardiovascular Center, 1500 East Medical Center Drive, SPC 5853, Ann Arbor, MI, 48109-5853, USA., Rosenson RS; Metabolism and Lipids Unit, Icahn School of Medicine at Mount Sinai, Cardiovascular Institute, Marie-Josee and Henry R Kravis Center for Cardiovascular Health, Mount Sinai, NY, USA., Pinsky DJ; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.; University of Michigan Frankel Cardiovascular Center, 1500 East Medical Center Drive, SPC 5853, Ann Arbor, MI, 48109-5853, USA., Haus JM; School of Kinesiology, University of Michigan, Ann Arbor, MI, USA., Hummel SL; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.; University of Michigan Frankel Cardiovascular Center, 1500 East Medical Center Drive, SPC 5853, Ann Arbor, MI, 48109-5853, USA.; VA Ann Arbor Health System, Ann Arbor, MI, USA., Goonewardena SN; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. sngoonew@med.umich.edu.; University of Michigan Frankel Cardiovascular Center, 1500 East Medical Center Drive, SPC 5853, Ann Arbor, MI, 48109-5853, USA. sngoonew@med.umich.edu.; VA Ann Arbor Health System, Ann Arbor, MI, USA. sngoonew@med.umich.edu.
Jazyk: angličtina
Zdroj: Cardiovascular drugs and therapy [Cardiovasc Drugs Ther] 2024 Apr; Vol. 38 (2), pp. 305-313. Date of Electronic Publication: 2022 Oct 19.
DOI: 10.1007/s10557-022-07390-4
Abstrakt: Purpose: Acute heart failure (AHF) syndromes manifest increased inflammation and vascular dysfunction; however, mechanisms that integrate the two in AHF remain largely unknown. The glycocalyx (GAC) is a sugar-based shell that envelops all mammalian cells. Much GAC research has focused on its role in vascular responses, with comparatively little known about how the GAC regulates immune cell function.
Methods: In this study, we sought to determine if GAC degradation products are elevated in AHF patients, how these degradation products relate to circulating inflammatory mediators, and whether the monocyte GAC (mGAC) itself modulates monocyte activation. Inflammatory markers and GAC degradation products were profiled using ELISAs. Flow cytometry was used to assess the mGAC and RNA-seq was employed to understand the role of the mGAC in regulating inflammatory activation programs.
Results: In a cohort of hospitalized AHF patients (n = 17), we found that (1) the GAC degradation product heparan sulfate (HS) was elevated compared with age-matched controls (4396 and 2903 ng/mL; p = 0.01) and that (2) HS and soluble CD14 (a marker of monocyte activation) levels were closely related (Pearson's r = 0.65; p = 0.002). Mechanistically, Toll-like receptor (TLR) activation of human monocytes results in GAC remodeling and a decrease in the mGAC (71% compared with no treatment; p = 0.0007). Additionally, we found that ex vivo enzymatic removal of HS and disruption of the mGAC triggers human monocyte activation and amplifies monocyte inflammatory responses. Specifically, using RNA-seq, we found that enzymatic degradation of the mGAC increases transcription of inflammatory (IL6, CCL3) and vascular (tissue factor/F3) mediators.
Conclusion: These studies indicate that the mGAC is dynamically remodeled during monocyte activation and that mGAC remodeling itself may contribute to the heightened inflammation associated with AHF.
(© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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