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

Front Immunol. 2024 Feb 12:15:1286382. doi: 10.3389/fimmu.2024.1286382. eCollection 2024.

Abstract

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.

Keywords: circulating monocytes; coronary artery disease; gene regulatory network; hypertension; inflammatory responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arteries / metabolism
  • Coronary Artery Disease* / metabolism
  • Gene Regulatory Networks
  • Humans
  • Hypertension* / genetics
  • Kruppel-Like Transcription Factors / genetics
  • Lipopolysaccharides / pharmacology
  • Monocytes / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Serine / metabolism
  • Threonine / genetics

Substances

  • Lipopolysaccharides
  • Serine
  • Threonine
  • STK33 protein, human
  • Protein Serine-Threonine Kinases
  • ZNF12 protein, human
  • Kruppel-Like Transcription Factors

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was funded by the Center for Translational Molecular Medicine (www.ctmm.nl), project CIRCULATING CELLS (grant 01C-102) and the China Scholarship Council (CSC) (no. 201706990018 to CL).