BIRC3 activates NF-κB to drive TNF-α-induced endothelial dysfunction in atherosclerosis

Atherosclerosis, a chronic inflammatory arteriopathy, constitutes a principal contributor to cardiovascular events. Its pathogenesis commences with endothelial dysfunction elicited by pro-inflammatory mediators like TNF-α. The exact involvement of BIRC3 (cIAP2) in this process remains largely uncharacterized. This study investigated whether BIRC3 contributes to TNF-α-induced endothelial injury via NF-κB signaling. Human aortic endothelial cells (HAECs) exposed to TNF-α exhibited markedly upregulated BIRC3 expression, concomitantly with NF-κB pathway activation. Silencing BIRC3 suppressed IκBα phosphorylation and p65 nuclear translocation and attenuated endothelial dysfunction, as evidenced by reduced levels of interleukin-6, interleukin-1β, VCAM-1, reactive oxygen species, and malondialdehyde, along with decreased apoptosis and a favorable Bax/Bcl-2 ratio. Conversely, BIRC3 overexpression exacerbated these pathological changes. Importantly, the deleterious effects of BIRC3 overexpression were largely reversed by co-treatment with the NF-κB inhibitor BAY 11-7082, indicating that BIRC3 drives TNF-α-mediated endothelial dysfunction in a strictly NF-κB-dependent manner. Collectively, our results identify BIRC3 as a positive regulator of TNF-α-induced endothelial injury and suggest that targeting BIRC3 may offer a novel avenue for alleviating endothelial dysfunction and hindering atherosclerotic progression.