Figure 9.

Proposed mechanism by which TNFα promotes vascular calcification. TNFα activates the PERK‐eIF2α‐ATF4‐CHOP axis of the ER stress signaling. TNFα also activates both PKA and RSK2, which in turn activate ATF4. Activation of ATF4 increases CHOP expression, leading to an increase in inorganic phosphate uptake by inducing a type III sodium‐dependent phosphate transporter, Pit‐1. Mechanism of ER stress activation by TNFα is unknown. ATF4 indicates activating transcription factor 4; CHOP, C/EBP homologous protein; ER, endoplasmic reticulum; eIF2α, eukaryotic initiation factor 2α; PERK, protein kinase RNA‐like endoplasmic reticulum kinase; Pi, inorganic phosphate; Pit‐1, sodium‐dependent phosphate transporter 1; PKA, protein kinase A; RSK2, ribosomal S6 kinase 2; Ser, serine; TNFα, tumor necrosis factor‐α.