Dietary Apigenin Reduces Induction of LOX-1 and NLRP3 Expression, Leukocyte Adhesion, and Acetylated Low-Density Lipoprotein Uptake in Human Endothelial Cells Exposed to Trimethylamine-N-Oxide.

Abstract

By inducing vascular inflammation, trimethylamine-N-oxide (TMAO) is associated with endothelial dysfunction, atherosclerosis, and enhanced risk of cardiovascular diseases in humans. However, the underlying mechanisms are unknown. Expression of several genes related to arteriosclerosis, inflammasomes, and endothelial dysfunction was quantified by polymerase chain reaction after exposure to TMAO. LOX-1, ICAM-1, and NLRP3 were also quantified by Western blot, whereas leukocytic adhesion was examined using fluorescently labeled U937 cells. Scavenger receptors, adhesion molecules, and other genes associated with atherosclerosis were induced in endothelial cells exposed to TMAO. On the other hand, apigenin, a flavonoid that is abundant in parsley and celery, prevents initial arteriosclerosis events in endothelial cells. Apigenin reversed the effects of TMAO on mRNA expression of LOX-1, SREC, SR-PSOX, NLRP3, ASC, TXNIP, VCAM-1, ICAM-1, and MCP-1, as well as protein expression of LOX-1, the adhesion molecule ICAM-1, and the inflammasome protein NLRP3. Apigenin also suppressed leukocyte adhesion and uptake of acetylated low-density lipoprotein. The data indicate that expression of scavenger receptors and adhesion molecules in response to TMAO, along with formation of NLRP3 inflammasomes, may drive endothelial dysfunction through uptake of acetylated low-density lipoprotein and lymphocyte adhesion. Apigenin reverses these effects, implying that it may also prevent arteriosclerosis.