Abstract:
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.
journal_name
J Am Heart Assocjournal_title
Journal of the American Heart Associationauthors
Masuda M,Miyazaki-Anzai S,Levi M,Ting TC,Miyazaki Mdoi
10.1161/JAHA.113.000238subject
Has Abstractpub_date
2013-09-05 00:00:00pages
e000238issue
5issn
2047-9980pii
jah3298journal_volume
2pub_type
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