To test our hypothesis that proatherogenic
lysophosphatidylcholine (LPC) upregulates trained immunity pathways (
TIPs) in human aortic endothelial cells (HAECs), we conducted an intensive analyses on our
RNA-Seq data and
histone 3
lysine 14 acetylation (H3K14ac)-CHIP-Seq data, both performed on HAEC treated with LPC. Our analysis revealed that: 1) LPC induces upregulation of three
TIPs including glycolysis
enzymes (GE),
mevalonate enzymes (ME), and
acetyl-CoA generating
enzymes (ACE); 2) LPC induces upregulation of 29% of 31
histone acetyltransferases, three of which acetylate H3K14; 3) LPC induces H3K14 acetylation (H3K14ac) in the genomic
DNA that encodes LPC-induced TIP genes (79%) in comparison to that of in LPC-induced effector genes (43%) including ICAM-1; 4) TIP pathways are significantly different from that of EC activation effectors including adhesion molecule ICAM-1; 5)
reactive oxygen species generating
enzyme NOX2 deficiency decreases, but
antioxidant transcription factor Nrf2 deficiency increases, the expressions of a few TIP genes and EC activation effector genes; and 6) LPC induced TIP genes(81%) favor inter-chromosomal long-range interactions (CLRI, trans-
chromatin interaction) while LPC induced effector genes (65%) favor intra-chromosomal CLRIs (cis-
chromatin interaction). Our findings demonstrated that proatherogenic
lipids upregulate
TIPs in HAECs, which are a new category of qualification markers for
chronic disease risk factors and conditional DAMPs and potential mechanisms for acute
inflammation transition to chronic ones. These novel insights may lead to identifications of new cardiovascular risk factors in upregulating
TIPs in cardiovascular cells and novel therapeutic targets for the treatment of metabolic
cardiovascular diseases,
inflammation, and
cancers. (total words: 245).