Epigenetic Modulation by Apabetalone Counters Cytokine-Driven Acute Phase Response In Vitro, in Mice and in Patients with Cardiovascular Disease

Table 1

Apabetalone downregulates transcriptional targets of inflammatory mediators in the CAD patient plasma as predicted by IPA® “canonical pathway” and “upstream regulators” analysis.

Ingenuity® Pathway Analysis	Pathway/regulator^a	Activation -score^b	value of overlap^c	Target molecules in dataset (gene symbols)^d
Canonical pathway	APR signaling	-2.1		C4A/C4B, C3, IL1RN, CRP, MAPK9, FGA/FGB/FGG, AGT
Upstream regulators	LPS	-3.1		ADIPOQ, AGT, BCL6, C3, CCL18, CCL5, CDH1, CDH5, CRP, CSF1R, EREG, FGA/FGB/FGG, IL1RN, IL2, KIT, MAPK9, MB, MMP10, NCR3, POMC, SPP1, TIMP2, TNFSF14, VTN
Upstream regulators	IL-6	-2.6		AGT, BCL6, C3, CCL5, CDH1, CDKN1B, CRP, EREG, FGA/FGB/FGG, GCG, IGFBP6, IL1RN, IL2, KIT, MMP10, POMC, SPP1
Upstream regulators	IFNG	-2.6		ADIPOQ, AGT, C3, C4A/C4B, CCL18, CCL5, CDH1, CDKN1B, CSF1R, CTSD, ERAP1, FGA/FGB/FGG, IL1RN, IL2, MMP10, NCR3, POMC, SPP1, TNFSF12
Upstream regulators	OSM	-2.0		CCL5, SPP1, MMP10, IGFBP6, FGA/FGB/FGG, CDKN1B, CDH1, CRP, POMC
Upstream regulators	IL1A	-2.0		CCL5, IL1RN, IL2, KIT, MMP10, POMC, SPP1
Upstream regulators	NFKB1	-1.8		CCL5, CRP, FGA/FGB/FGG, IL1RN, IL2, MMP10

Plasma proteins affected by apabetalone treatment by more than 10% (versus placebo, ) were analyzed with the IPA® “canonical pathway” and “upstream regulator” analytics. ^aAPR: acute phase response; LPS: lipopolysaccharide; IL-6: interleukin 6; IFNG: interferon γ; OSM: oncostatin M; IL1A: interleukin 1α; NFKB1: nuclear factor κB subunit 1. ^bIPA® z-score compares the observed differential regulation of a gene in the dataset to changes predicted by the literature which can be either “activating” or “inhibiting.” predicts downregulation within a gene set associated with a transcriptional regulator. ^cThe overlap value measures whether there is a statistically significant overlap between the dataset genes and the genes that are regulated by a transcriptional regulator. It is calculated using Fisher’s exact test, and significance is attributed to values < 0.01. ^dApabetalone target proteins that contribute to IPA® “canonical pathways” or “upstream regulators” are listed as gene symbols.