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Updated: May 8, 2026

Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation
Published on: May 31, 2016
PERK-eIF2α-ATF4-CHOP signaling contributes to TNFα-induced vascular calcification
Masashi Masuda1, Shinobu Miyazaki-Anzai, Moshe Levi
1Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO.
Background:
Vascular calcification is a common feature in patients with chronic kidney disease (CKD). CKD increases serum levels of tumor necrosis factor-α (TNFα), a critical mediator of vascular calcification. However, the molecular mechanism by which TNFα promotes CKD-dependent vascular calcification remains obscure. The purpose of the present study was to investigate whether TNFα-induced vascular calcification in CKD is caused by the endoplasmic reticulum response involving protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP).
Methods And Results:
We examined the effects of TNFα on the endoplasmic reticulum (ER) stress response of vascular smooth muscle cells (VSMCs). TNFα treatment drastically induced the PERK-eIF2α-ATF4-CHOP axis of the ER stress response in VSMCs. PERK, ATF4, and CHOP shRNA-mediated knockdowns drastically inhibited mineralization and osteogenesis of VSMCs induced by TNFα. CKD induced by 5/6 nephrectomies activated the PERK-eIF2α-ATF4-CHOP axis of the ER stress response in the aortas of ApoE-/- mice with increased aortic TNFα expression and vascular calcification. Treatment of 5/6 nephrectomized ApoE-/- mice with the TNFα neutralizing antibody or chemical Chaperones reduced aortic PERK-eIF2α-ATF4-CHOP signaling of the ER stress increased by CKD. This resulted in the inhibition of CKD-dependent vascular calcification.
Conclusions:
These results suggest that TNFα induces the PERK-eIF2α-ATF4-CHOP axis of the ER stress response, leading to CKD-dependent vascular calcification.
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