Vascular calcification in CKD: New insights into its mechanisms

Ding, Nannan; Lv, Yaodong; Hong, Soon-Kwang; Wang, Ziyang; Kong, Xianglei; Zhen, Junhui; Lv, Zhimei; Wang, Rong

doi:10.1002/jcp.31021

Cited by 8 publications

(6 citation statements)

References 185 publications

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“…For example, the abnormal calciumphosphate homeostasis, inflammation, oxidative stress, and dysregulation of FGF23-Klotho axis is shown to involved in pathogenesis of vascular calcification. 22 Previous studies have shown that both high phosphate and oxidative stress have impacts on HDAC2 expression at transcriptional or posttranscriptional level. 23,24 Therefore, we speculated that increased phosphate in CKD might be a major cause of the reduction of HDAC2 in VSMCs of the artery.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the vascular calcification in CKD is a consequence of multiple risk factors. For example, the abnormal calcium‐phosphate homeostasis, inflammation, oxidative stress, and dysregulation of FGF23‐Klotho axis is shown to involved in pathogenesis of vascular calcification 22 . Previous studies have shown that both high phosphate and oxidative stress have impacts on HDAC2 expression at transcriptional or posttranscriptional level 23,24 .…”

Section: Discussionmentioning

confidence: 99%

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HDAC2 counteracts vascular calcification by activating autophagy in chronic kidney disease

Zhou,

Liu,

Zhang

et al. 2024

The FASEB Journal

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Vascular calcification is a major risk factor for cardiovascular disease mortality, with a significant prevalence in chronic kidney disease (CKD). Pharmacological inhibition of histone acetyltransferase has been proven to protect against from vascular calcification. However, the role of Histone Deacetylase 2 (HDAC2) and molecular mechanisms in vascular calcification of CKD remains unknown. An in vivo model of CKD was established using mouse fed with a high adenine and phosphate diet, and an in vitro model was produced using human aortic vascular smooth muscle cells (VSMCs) stimulated with β‐glycerophosphate (β‐GP). HDAC2 expression was found to be reduced in medial artery of CKD mice and β‐GP‐induced VSMCs. Overexpression of HDAC2 attenuated OPN and OCN upregulation, α‐SMA and SM22α downregulation, and calcium deposition in aortas of CKD. The in vitro results also demonstrated that β‐GP‐induced osteogenic differentiation was inhibited by HDAC2. Furthermore, we found that HDAC2 overexpression caused an increase in LC3II/I, a decrease in p62, and an induction of autophagic flux. Inhibition of autophagy using its specific inhibitor 3‐MA blocked HDAC2's protective effect on osteogenic differentiation in β‐GP‐treated VSMCs. Taken together, these results suggest that HDAC2 may protect against vascular calcification by the activation of autophagy, laying out a novel insight for the molecular mechanism in vascular calcification of CKD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

HDAC2 counteracts vascular calcification by activating autophagy in chronic kidney disease

Zhou,

Liu,

Zhang

et al. 2024

The FASEB Journal

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“…Recent advancements highlight abnormalities in epigenetic modifications (such as DNA methylation, histone modifications, and noncoding RNAs), ferroptosis of VSMCs, autophagy dysfunction, and senescence as active participants in the cellular processes leading to VC ( 12 , 20 , 21 ). Extensive studies have delved into the involvement of senescent vascular cells, including VECs, VSMCs, and macrophages, in propagating senescence through paracrine mechanisms (e.g., SASP and MV) ( 22 – 24 ).…”

Section: Vascular Calcificationmentioning

confidence: 99%

The functional role of cellular senescence during vascular calcification in chronic kidney disease

Fang,

Zhao,

Huang

et al. 2024

Front. Endocrinol.

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Vascular calcification (VC) has emerged as a key predictor of cardiovascular events in patients with chronic kidney disease (CKD). In recent years, an expanding body of research has put forth the concept of accelerated vascular aging among CKD patients, highlighting the significance of vascular cells senescence in the process of VC. Within the milieu of uremia, senescent vascular endothelial cells (VECs) release extracellular microvesicles (MV) that promote vascular smooth muscle cells (VSMCs) senescence, thereby triggering the subsequent osteogenic phenotypic switch and ultimately contributing to the VC process. In addition, senescent vascular progenitor or stem cells with diminished ability to differentiate into VECs and VSMCS, compromise the repair of vascular integrity, on the other hand, release a cascade of molecules associated with senescence, collectively known as the senescence-associated secretory phenotype (SASP), perpetuating the senescence phenomenon. Furthermore, SASP triggers the recruitment of monocytes and macrophages, as well as adjacent VECs and VSMCs into a pro-adhesive and pro-inflammatory senescent state. This pro-inflammatory microenvironment niche not only impacts the functionality of immune cells but also influences the differentiation of myeloid immune cells, thereby amplifying the reduced ability to effectively clear senescent cells of senescent macrophages, promoted calcification of VSMCs. The objective of this paper is to provide a comprehensive review of the contribution of vascular cell senescence to the emergence and advancement of VC. Gaining a comprehensive understanding of the involvement of cellular senescence within the vessel wall is pivotal, especially when it comes to its intersection with VC. This knowledge is essential for advancing groundbreaking anti-aging therapies, aiming to effectively mitigate cardiovascular diseases.

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“…Vascular calcification (VC) is a pathological process characterised by the deposition of hydroxyapatite crystals in the layer of the arterial wall that increases the risk of cardiovascular (CV) events [1]. VC is a hallmark of vascular remodelling induced by physiological ageing, diabetes, atherosclerosis, and chronic kidney disease (CKD) [1][2][3]. Anatomically, there are two types of VC.…”

Section: Introductionmentioning

confidence: 99%

High Phosphate-Induced JAK-STAT Signalling Sustains Vascular Smooth Muscle Cell Inflammation and Limits Calcification

Macrì,

Vigorito,

Castiglione

et al. 2023

Biomolecules

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Vascular calcification (VC) is an age-related complication characterised by calcium-phosphate deposition in the arterial wall driven by the osteogenic transformation of vascular smooth muscle cells (VSMCs). The JAK-STAT pathway is an emerging target in inflammation. Considering the relationship between VC and inflammation, we investigated the role of JAK-STAT signalling during VSMC calcification. Human aortic smooth muscle cells (HASMCs) were cultured in high-inorganic phosphate (Pi) medium for up to 7 days; calcium deposition was determined via Alizarin staining and colorimetric assay. Inflammatory factor secretion was evaluated via ELISA and JAK-STAT members’ activation using Western blot or immunohistochemistry on HASMCs or calcified aortas of Vitamin D-treated C57BL6/J mice, respectively. The JAK-STAT pathway was blocked by JAK Inhibitor I and Von Kossa staining was used for calcium deposits in murine aortic rings. During Pi-induced calcification, HASMCs released IL-6, IL-8, and MCP-1 and activated JAK1-JAK3 proteins and STAT1. Phospho-STAT1 was detected in murine calcified aortas. Blocking of the JAK-STAT cascade reduced HASMC proliferation and pro-inflammatory factor expression and release while increasing calcium deposition and osteogenic transcription factor RUNX2 expression. Consistently, JAK-STAT pathway inhibition exacerbates mouse aortic ring calcification ex vivo. Intriguingly, our results suggest an alternative link between VSMC inflammation and VC.

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Vascular calcification in CKD: New insights into its mechanisms

Cited by 8 publications

References 185 publications

HDAC2 counteracts vascular calcification by activating autophagy in chronic kidney disease

HDAC2 counteracts vascular calcification by activating autophagy in chronic kidney disease

The functional role of cellular senescence during vascular calcification in chronic kidney disease

High Phosphate-Induced JAK-STAT Signalling Sustains Vascular Smooth Muscle Cell Inflammation and Limits Calcification

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