Human monocyte inflammation in patients with Lp(a) or atherosclerotic cardiovascular disease is not accompanied by changes in chromatin accessibility in circulating classical monocytes.

Abstract

Background and aims: High plasma lipoprotein(a) [Lp(a)] levels are associated with accelerated atherosclerosis and subsequent atherosclerotic cardiovascular disease (ASCVD), potentially through enhanced inflammatory signaling of monocytes. Given that monocytes are major players in ASCVD risk and the role of epigenetic changes in regulating their responsiveness, we propose that investigating changes in chromatin accessibility could reveal the underlying mechanisms of enhanced monocyte inflammation.

Methods: In this observational case-control study, we collected blood from subjects with low (<25 nmol/L) and elevated (>350 nmol/L) plasma Lp(a) with and without a history of ASCVD, matched for age and sex. A total of 60 subjects were included in the study, comprising 60% males and a mean age of 62.8 ± 7.8 years. We assessed gene expression and chromatin accessibility of fluorescence-activated cell sorting (FACS)-sorted classical monocytes using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and bulk assay for transposase-accessible chromatin (ATAC)-sequencing and analyzed plasma cytokine levels.

Results: Subjects with high plasma Lp(a) showed significantly increased gene expression of IFIT3. At the plasma level, subjects with high Lp(a) without ASCVD were distinguished by higher concentrations of chemokine C-X-C motif ligand 10 (CXCL10). While these results are consistent with previous research demonstrating increased interferon-γ signaling in monocytes of individuals with elevated Lp(a), we did not detect differences in chromatin accessibility of monocytes between subjects with high or low Lp(a), irrespective of ASCVD status.

Conclusion: While subjects with high Lp(a) levels showed enhanced monocyte inflammation, no differences in chromatin accessibility were detected. This suggests that the pro-inflammatory signature of Lp(a) and ASCVD on monocytes is regulated at a level other than chromatin accessibility.