IL-6 induces mitochondrial ROS production and blunts NO bioavailability in human aortic endothelial cells.

Chronic inflammation is a major contributor to the development of endothelial dysfunction. Circulating concentrations of the proinflammatory cytokine interleukin-6 (IL-6) have been shown to predict cardiovascular disease risk and are associated with the development of vascular dysfunction. However, the mechanisms that underlie inflammation-induced endothelial dysfunction are not fully understood. Vascular endothelial dysfunction is characterized by blunted nitric oxide (NO) bioavailability and increased reactive oxygen species (ROS), with mitochondrial ROS suggested to play a primary role. Therefore, we tested the hypothesis that IL-6 induces mitochondrial ROS production and blunts NO bioavailability in endothelial cells. To study the effect of IL-6, we treated the human aortic endothelial cells (HAECs) with IL-6, MitoTEMPOL (MT; a mitochondria-targeted antioxidant), and/or a nitric oxide synthase (NOS) inhibitor (l-NAME) with and without ACh stimulation. Results are expressed as means ± SD (n = 4 replicates), one-way ANOVA, and Bonferroni's post hoc tests were performed. IL-6 treatment resulted in greater mitochondrial ROS (IL-6: 2.94 ± 0.93 a.u.) when compared with the untreated cells (Control: 1 ± 0; P = 0.0021) and also blunted NO bioavailability at baseline (Control: 1 ± 0; IL-6: 0.57 ± 0.08 a.u. P = 0.0008) and with acetylcholine stimulation (Control Ach: 1.27 ± 0.09; IL-6 Ach: 0.60 ± 0.13 a.u. P < 0.0001). Scavenging mitochondrial ROS with MT restored NO bioavailability in the IL-6-treated cells (IL-6: 0.57 ± 0.08; IL-6 MT: 1.16 ± 0.20 a.u. P < 0.0001). These findings indicate that IL-6 has a direct effect on mitochondrial ROS in human aortic endothelial cells, which leads to reduced nitric oxide bioavailability.NEW & NOTEWORTHY In this study, we provide evidence that IL-6 induces mitochondrial ROS production, which impairs nitric oxide bioavailability in human aortic endothelial cells. This finding adds an important perspective to the existing literature on the mechanism by which IL-6 contributes to endothelial dysfunction.