Identification of a gene network driving the attenuated response to lipopolysaccharide of monocytes from hypertensive...

Area of Science:

• Immunology
• Cardiovascular Medicine
• Genomics

Background:

• Cardiovascular disease (CVD) risk factors impact circulating monocyte function, a key player in CVD.
• The precise influence of CVD risk factors on monocyte transcriptional responses to infection is not fully understood.

Purpose of the Study:

• To investigate how CVD risk factors affect monocyte gene expression after an infectious stimulus.
• To identify molecular mechanisms linking CVD risk factors to altered monocyte function.

Main Methods:

• Comparative analysis of monocyte gene expression profiles in coronary artery disease (CAD) patients before and after lipopolysaccharide (LPS) stimulation.
• Gene co-expression analysis to correlate gene modules with CVD risk factors.
• Regulatory network analysis to identify key transcription factors.
• Drug repurposing screen using the LINCS L1000 database.

Main Results:

• Monocyte responsiveness to LPS negatively correlated with blood pressure (P<10⁻⁸⁰).
• A ZNF12/ZBTB43-driven gene module linked to diastolic blood pressure was identified.
• Monocyte responses to LPS were attenuated in CAD patients with high diastolic blood pressure, linked to suppressed oxidative phosphorylation.
• The serine-threonine inhibitor MW-STK33-97 was identified as a potential therapeutic to reverse this response.

Conclusions:

• Monocyte inflammatory responses to infection may be impaired in CAD patients with elevated diastolic blood pressure.
• The identified aberrant monocyte response could potentially be reversed by MW-STK33-97.
• Further research is needed to determine if the identified gene module is causal or merely indicative of diastolic blood pressure and dampened LPS responses.