Cargando…

Impaired intracellular calcium homeostasis enhances protein O-GlcNAcylation and promotes vascular calcification and stiffness in diabetes

Vascular calcification is accelerated in patients with diabetes mellitus and increases risk of cardiovascular events and mortality. Vascular smooth muscle cells (VSMC) play a key role in regulating vascular tone and contribute significantly to the development of diabetic vasculopathy. In this study,...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Weiping, Sun, Yong, Yang, Youfeng, Chen, Yabing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10225928/
https://www.ncbi.nlm.nih.gov/pubmed/37230005
http://dx.doi.org/10.1016/j.redox.2023.102720
_version_ 1785050478686502912
author Zhang, Weiping
Sun, Yong
Yang, Youfeng
Chen, Yabing
author_facet Zhang, Weiping
Sun, Yong
Yang, Youfeng
Chen, Yabing
author_sort Zhang, Weiping
collection PubMed
description Vascular calcification is accelerated in patients with diabetes mellitus and increases risk of cardiovascular events and mortality. Vascular smooth muscle cells (VSMC) play a key role in regulating vascular tone and contribute significantly to the development of diabetic vasculopathy. In this study, the function of stromal interaction molecule 1 (STIM1), an important regulator for intracellular calcium homeostasis, in diabetic vascular calcification was investigated, and the underlying molecular mechanisms were uncovered. A SMC-specific STIM1 deletion mouse model (STIM1(Δ/Δ)) was generated by breeding the STIM1 floxed mice (STIM1(f/f)) with SM22α-Cre transgenic mice. Using aortic arteries from the STIM1(Δ/Δ) mice and their STIM1(f/f) littermates, we found that SMC-specific STIM1 deletion induced calcification of aortic arteries cultured in osteogenic media ex vivo. Furthermore, STIM1 deficiency promoted osteogenic differentiation and calcification of VSMC from the STIM1(Δ/Δ) mice. In the low-dose streptozotocin (STZ)-induced mouse model of diabetes, SMC-specific STIM1 deletion markedly enhanced STZ-induced vascular calcification and stiffness in the STIM1(Δ/Δ) mice. The diabetic mice with SMC-specific STIM1 ablation also exhibited increased aortic expression of the key osteogenic transcription factor, Runx2, and protein O-GlcNAcylation, an important post-translational modulation that we have reported to promote vascular calcification and stiffness in diabetes. Consistently, elevation of O-GlcNAcylation was demonstrated in aortic arteries and VSMC from the STIM1(Δ/Δ) mice. Inhibition of O-GlcNAcylation with a pharmacological inhibitor abolished STIM1 deficiency-induced VSMC calcification, supporting a critical role of O-GlcNAcylation in mediating STIM1 deficiency-induced VSMC calcification. Mechanistically, we identified that STIM1 deficiency resulted in impaired calcium homeostasis, which activated calcium signaling and increased endoplasmic reticulum (ER) stress in VSMC, while inhibition of ER stress attenuated STIM1-induced elevation of protein O-GlcNAcylation. In conclusion, the study has demonstrated a causative role of SMC-expressed STIM1 in regulating vascular calcification and stiffness in diabetes. We have further identified a novel mechanisms underlying STIM1 deficiency-induced impairment of calcium homeostasis and ER stress in upregulation of protein O-GlcNAcylation in VSMC, which promotes VSMC osteogenic differentiation and calcification in diabetes.
format Online
Article
Text
id pubmed-10225928
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-102259282023-05-30 Impaired intracellular calcium homeostasis enhances protein O-GlcNAcylation and promotes vascular calcification and stiffness in diabetes Zhang, Weiping Sun, Yong Yang, Youfeng Chen, Yabing Redox Biol Research Paper Vascular calcification is accelerated in patients with diabetes mellitus and increases risk of cardiovascular events and mortality. Vascular smooth muscle cells (VSMC) play a key role in regulating vascular tone and contribute significantly to the development of diabetic vasculopathy. In this study, the function of stromal interaction molecule 1 (STIM1), an important regulator for intracellular calcium homeostasis, in diabetic vascular calcification was investigated, and the underlying molecular mechanisms were uncovered. A SMC-specific STIM1 deletion mouse model (STIM1(Δ/Δ)) was generated by breeding the STIM1 floxed mice (STIM1(f/f)) with SM22α-Cre transgenic mice. Using aortic arteries from the STIM1(Δ/Δ) mice and their STIM1(f/f) littermates, we found that SMC-specific STIM1 deletion induced calcification of aortic arteries cultured in osteogenic media ex vivo. Furthermore, STIM1 deficiency promoted osteogenic differentiation and calcification of VSMC from the STIM1(Δ/Δ) mice. In the low-dose streptozotocin (STZ)-induced mouse model of diabetes, SMC-specific STIM1 deletion markedly enhanced STZ-induced vascular calcification and stiffness in the STIM1(Δ/Δ) mice. The diabetic mice with SMC-specific STIM1 ablation also exhibited increased aortic expression of the key osteogenic transcription factor, Runx2, and protein O-GlcNAcylation, an important post-translational modulation that we have reported to promote vascular calcification and stiffness in diabetes. Consistently, elevation of O-GlcNAcylation was demonstrated in aortic arteries and VSMC from the STIM1(Δ/Δ) mice. Inhibition of O-GlcNAcylation with a pharmacological inhibitor abolished STIM1 deficiency-induced VSMC calcification, supporting a critical role of O-GlcNAcylation in mediating STIM1 deficiency-induced VSMC calcification. Mechanistically, we identified that STIM1 deficiency resulted in impaired calcium homeostasis, which activated calcium signaling and increased endoplasmic reticulum (ER) stress in VSMC, while inhibition of ER stress attenuated STIM1-induced elevation of protein O-GlcNAcylation. In conclusion, the study has demonstrated a causative role of SMC-expressed STIM1 in regulating vascular calcification and stiffness in diabetes. We have further identified a novel mechanisms underlying STIM1 deficiency-induced impairment of calcium homeostasis and ER stress in upregulation of protein O-GlcNAcylation in VSMC, which promotes VSMC osteogenic differentiation and calcification in diabetes. Elsevier 2023-05-17 /pmc/articles/PMC10225928/ /pubmed/37230005 http://dx.doi.org/10.1016/j.redox.2023.102720 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Zhang, Weiping
Sun, Yong
Yang, Youfeng
Chen, Yabing
Impaired intracellular calcium homeostasis enhances protein O-GlcNAcylation and promotes vascular calcification and stiffness in diabetes
title Impaired intracellular calcium homeostasis enhances protein O-GlcNAcylation and promotes vascular calcification and stiffness in diabetes
title_full Impaired intracellular calcium homeostasis enhances protein O-GlcNAcylation and promotes vascular calcification and stiffness in diabetes
title_fullStr Impaired intracellular calcium homeostasis enhances protein O-GlcNAcylation and promotes vascular calcification and stiffness in diabetes
title_full_unstemmed Impaired intracellular calcium homeostasis enhances protein O-GlcNAcylation and promotes vascular calcification and stiffness in diabetes
title_short Impaired intracellular calcium homeostasis enhances protein O-GlcNAcylation and promotes vascular calcification and stiffness in diabetes
title_sort impaired intracellular calcium homeostasis enhances protein o-glcnacylation and promotes vascular calcification and stiffness in diabetes
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10225928/
https://www.ncbi.nlm.nih.gov/pubmed/37230005
http://dx.doi.org/10.1016/j.redox.2023.102720
work_keys_str_mv AT zhangweiping impairedintracellularcalciumhomeostasisenhancesproteinoglcnacylationandpromotesvascularcalcificationandstiffnessindiabetes
AT sunyong impairedintracellularcalciumhomeostasisenhancesproteinoglcnacylationandpromotesvascularcalcificationandstiffnessindiabetes
AT yangyoufeng impairedintracellularcalciumhomeostasisenhancesproteinoglcnacylationandpromotesvascularcalcificationandstiffnessindiabetes
AT chenyabing impairedintracellularcalciumhomeostasisenhancesproteinoglcnacylationandpromotesvascularcalcificationandstiffnessindiabetes