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Identification of a gene network driving the attenuated response to lipopolysaccharide of monocytes from hypertensive coronary artery disease patients

Lu, Chang (författare)
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands; Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany
Donners, Marjo M.P.C. (författare)
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands
de Baaij, Julius B.J. (författare)
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands
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Jin, Han (författare)
KTH,Systembiologi,Science for Life Laboratory, SciLifeLab,ience for Life Laboratory, Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands
Otten, Jeroen J.T. (författare)
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands
Manca, Marco (författare)
SCimPulse Foundation, Geleen, Netherlands
van Zonneveld, Anton Jan (författare)
Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, Netherlands
Jukema, J. Wouter (författare)
Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands; Netherlands Heart Institute, Utrecht, Netherlands
Kraaijeveld, Adriaan (författare)
Department of Cardiology, University Medical Center Utrecht, Utrecht, Netherlands
Kuiper, Johan (författare)
Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
Pasterkamp, Gerard (författare)
Circulatory Health Research Center, University Medical Center Utrecht, Utrecht, Netherlands
Mees, Barend (författare)
Department of Vascular Surgery, Maastricht University Medical Center, Maastricht, Netherlands
Sluimer, Judith C. (författare)
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands; Centre for Cardiovascular Science (CVS), University of Edinburgh, Edinburgh, United Kingdom
Cavill, Rachel (författare)
Department of Advanced Computing Sciences, Maastricht University, Maastricht, Netherlands
Karel, Joël M.H. (författare)
Department of Advanced Computing Sciences, Maastricht University, Maastricht, Netherlands
Goossens, Pieter (författare)
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands
Biessen, Erik A.L. (författare)
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands; Institute for Molecular Cardiovascular Research, Klinikum RWTH Aachen, Aachen, Germany
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 (creator_code:org_t)
Frontiers Media SA, 2024
2024
Engelska.
Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 15
Relaterad länk:
https://doi.org/10.3...
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https://urn.kb.se/re...
https://doi.org/10.3...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • Introduction: The impact of cardiovascular disease (CVD) risk factors, encompassing various biological determinants and unhealthy lifestyles, on the functional dynamics of circulating monocytes—a pivotal cell type in CVD pathophysiology remains elusive. In this study, we aimed to elucidate the influence of CVD risk factors on monocyte transcriptional responses to an infectious stimulus. Methods: We conducted a comparative analysis of monocyte gene expression profiles from the CTMM – CIRCULATING CELLS Cohort of coronary artery disease (CAD) patients, at baseline and after lipopolysaccharide (LPS) stimulation. Gene co-expression analysis was used to identify gene modules and their correlations with CVD risk factors, while pivotal transcription factors controlling the hub genes in these modules were identified by regulatory network analyses. The identified gene module was subjected to a drug repurposing screen, utilizing the LINCS L1000 database. Results: Monocyte responsiveness to LPS showed a highly significant, negative correlation with blood pressure levels (ρ< -0.4; P<10-80). We identified a ZNF12/ZBTB43-driven gene module closely linked to diastolic blood pressure, suggesting that monocyte responses to infectious stimuli, such as LPS, are attenuated in CAD patients with elevated diastolic blood pressure. This attenuation appears associated with a dampening of the LPS-induced suppression of oxidative phosphorylation. Finally, we identified the serine-threonine inhibitor MW-STK33-97 as a drug candidate capable of reversing this aberrant LPS response. Conclusions: Monocyte responses to infectious stimuli may be hampered in CAD patients with high diastolic blood pressure and this attenuated inflammatory response may be reversed by the serine-threonine inhibitor MW-STK33-97. Whether the identified gene module is a mere indicator of, or causal factor in diastolic blood pressure and the associated dampened LPS responses remains to be determined.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kardiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)

Nyckelord

circulating monocytes
coronary artery disease
gene regulatory network
hypertension
inflammatory responses

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