Apoptosis signal-regulating kinase 1 activation by Nox1-derived oxidants is required for TNF α receptor endocytosis.

Apoptosis signal-regulating kinase 1 activation by Nox1-derived oxidants is required for TNFα receptor endocytosis. Am J Physiol Heart Circ Physiol. 2019 Mar 29;: Authors: Choi H, Stark RJ, Raja BS, Dikalova A, Lamb FS Abstract Tumor necrosis factor-α (TNFα) is pro-inflammatory cytokine that is closely linked to the development of cardiovascular disease. TNFα activates NADPH oxidase 1 (Nox1), and reactive oxygen species (ROS) including superoxide (O2•-) production extracellularly are required for subsequent signaling in vascular smooth muscle cells (VSMC). Apoptosis signal-regulating kinase 1 (ASK1) is a MAPKKK that is activated by oxidation of associated thioredoxin. The role of ASK1 in Nox1-mediated signaling by TNFα is poorly defined. We hypothesized that ASK1 is required for TNFα receptor endocytosis and subsequent inflammatory TNFα signaling. We employed a knockdown strategy to explore the role of ASK1 in TNFα signaling in VSMCs. Small interfering RNA (siRNA) targeting ASK1 had no effect on TNFα-induced extracellular O2•- production. However, siASK1 inhibited receptor endocytosis, as well as phosphorylation of two endocytosis-related proteins, dynamin1 and caveolin1. Intracellular O2•- production was subsequently reduced, as were other inflammatory signaling steps including; NF-κB activation, IL-6 production, iNOS and VCAM expression and VSMC proliferation. Prolonged exposure to TNFα (24 hours) increased TNFR su...
Source: American Journal of Physiology. Heart and Circulatory Physiology - Category: Physiology Authors: Tags: Am J Physiol Heart Circ Physiol Source Type: research