A strategy to prevent atherosclerosis via TNF receptor regulation

Abstract Atherosclerosis is a chronic inflammatory disease of the arterial wall. It has been known that development of atherosclerosis is closely related to activation of tumor necrosis factor α (TNF‐α). The objective of this study was to elucidate the effects of TNF‐α blockade with brusatol on endothelial activation under pro‐atherosclerotic conditions. To this end, we examined the effects of brusatol on TNF‐α‐induced intracellular adhesion molecule‐1 (ICAM‐1) and vascular cell adhesion molecule‐1 (VCAM‐1) expression in human aortic endothelial cells (HAECs) using western blot and THP‐1 adhesion assays. Brusatol induced a decrease in TNF‐α‐induced ICAM‐1 and VCAM‐1 expression through inhibiting TNFR1 expression, leading to suppression of endothelial inflammation independently of the NRF2 (nuclear factor erythroid 2‐related factor 2) pathway. The mechanism underlying brusatol‐induced TNF receptor 1 (TNFR1) inhibition was investigated with the aid of protein synthesis, co‐immunoprecipitation, and cytokine arrays. Notably, brusatol inhibited TNFR1 protein synthesis and suppressed both the canonical nuclear factor kappa‐light‐chain‐enhancer of activated B cell (NF‐κB) signaling pathway and TNF‐α‐induced cytokine secretion. We further tested the functional effect of brusatol on atherosclerosis development in vivo using two different atherosclerosis mouse models, specifically, acute partial carotid ligation and conventional chronic high‐fat diet‐fed mouse models. Administration of brusatol led to significant suppression of atherosclerosis development in both mouse models. Our finding that brusatol prevents atherosclerosis via inhibition of TNFR1 protein synthesis supports the potential of downregulation of cell surface TNFR1 as an effective therapeutic approach to inhibit development of atherosclerosis.