Pharmacological Inhibition of eIF2α Phosphorylation by Integrated Stress Response Inhibitor (ISRIB) Ameliorates Vascular Calcification in Rats

Vascular calcification (VC) is an independent risk factor for cardiovascular events and all-cause mortality with the absence of current treatment. This study aimed to investigate whether eIF2α phosphorylation inhibition could ameliorate VC. VC in rats was induced by administration of vitamin D3 (3×1...

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Published in:Physiological research 2022-06, Vol.71 (3), p.379-388
Main Authors: DONG, J, JIN, S, GUO, J, YANG, R, TIAN, D, XUE, H, XIAO, L, GUO, Q, WANG, R, XU, M, TENG, X, WU, Y
Format: Article
Language:English
Subjects:
Aorta
Apoptosis
Bioengineering
Blood pressure
Blood vessels
Calcification
Calcification (ectopic)
Calponin
Cardiovascular diseases
Catheters
Cbfa-1 protein
CCAAT/enhancer-binding protein
Coronary vessels
Endoplasmic reticulum
Hemodynamics
Homeostasis
Hypertension
Initiation factor eIF-2
Kinases
Laboratory animals
Nicotine
Phosphorylation
Prevention
Proteins
Risk factors
Veins & arteries
Vitamin D3
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Summary:Vascular calcification (VC) is an independent risk factor for cardiovascular events and all-cause mortality with the absence of current treatment. This study aimed to investigate whether eIF2α phosphorylation inhibition could ameliorate VC. VC in rats was induced by administration of vitamin D3 (3×105 IU/kg, intramuscularly) plus nicotine (25 mg/kg, intragastrically). ISRIB (0.25 mg/kg·week), an inhibitor of eIF2α phosphorylation, ameliorated the elevation of calcium deposition and ALP activity in calcified rat aortas, accompanied by amelioration of increased SBP, PP, and PWV. The decreased protein levels of calponin and SM22α, and the increased levels of RUNX2 and BMP2 in calcified aorta were all rescued by ISRIB, while the increased levels of the GRP78, GRP94, and C/EBP homologous proteins in rats with VC were also attenuated. Moreover, ISRIB could prevent the elevation of eIF2α phosphorylation and ATF4, and partially inhibit PERK phosphorylation in the calcified aorta. These results suggested that an eIF2α phosphorylation inhibitor could ameliorate VC pathogenesis by blocking eIF2α/ATF4 signaling, which may provide a new target for VC prevention and treatment.
ISSN:0862-8408
1802-9973
DOI:10.33549/physiolres.934797