Inhibition of extracellular matrix integrity attenuates the early phase of aortic medial calcification in a rodent model

Uto, Kenta; Yoshizawa, Saeko; Aoki, Chiharu; Nishikawa, Toshio; Oda, Hideaki

doi:10.1016/j.atherosclerosis.2020.12.015

Cited by 15 publications

(7 citation statements)

References 48 publications

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“…Intrinsic stiffness and extracellular matrix remodeling of VSMC contribute to osteogenic differentiation and calcification of VSMC, and ossification and calcification are closely related ( Chen, Zhao & Wu, 2020 ). Disruption of extracellular matrix integrity can attenuate medial aortic calcification in its early stages ( Uto et al, 2021 ). Upregulation of FOXO1/3 inhibits VC ( Deng et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of potential biomarkers of vascular calcification using bioinformatics analysis and validation in vivo

Chen

et al. 2022

PeerJ

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Background Vascular calcification (VC) is the most widespread pathological change in diseases of the vascular system. However, we know poorly about the molecular mechanisms and effective therapeutic approaches of VC. Methods The VC dataset, GSE146638, was downloaded from the Gene Expression Omnibus (GEO) database. Using the edgeR package to screen Differentially expressed genes (DEGs). Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used to find pathways affecting VC. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed on the DEGs. Meanwhile, using the String database and Cytoscape software to construct protein-protein interaction (PPI) networks and identify hub genes with the highest module scores. Correlation analysis was performed for hub genes. Receiver operating characteristic (ROC) curves, expression level analysis, GSEA, and subcellular localization were performed for each hub gene. Expression of hub genes in normal and calcified vascular tissues was verified by quantitative reverse transcription PCR (RT-qPCR) and immunohistochemistry (IHC) experiments. The hub gene-related miRNA-mRNA and TF-mRNA networks were constructed and functionally enriched for analysis. Finally, the DGIdb database was utilized to search for alternative drugs targeting VC hub genes. Results By comparing the genes with normal vessels, there were 64 DEGs in mildly calcified vessels and 650 DEGs in severely calcified vessels. Spp1, Sost, Col1a1, Fn1, and Ibsp were central in the progression of the entire VC by the MCODE plug-in. These hub genes are primarily enriched in ossification, extracellular matrix, and ECM-receptor interactions. Expression level results showed that Spp1, Sost, Ibsp, and Fn1 were significantly highly expressed in VC, and Col1a1 was incredibly low. RT-qPCR and IHC validation results were consistent with bioinformatic analysis. We found multiple pathways of hub genes acting in VC and identified 16 targeting drugs. Conclusions This study perfected the molecular regulatory mechanism of VC. Our results indicated that Spp1, Sost, Col1a1, Fn1, and Ibsp could be potential novel biomarkers for VC and promising therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Identification of potential biomarkers of vascular calcification using bioinformatics analysis and validation in vivo

Chen

et al. 2022

PeerJ

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“…Increased LOX activity has been shown to induce vascular calcification [22,23]. Here, TEM analysis of CD11b KO healthy cartilage revealed increased LOX immuno-gold labeling, mainly localized in the ECM rather in chondrocytes (Figure 5a,b).…”

Section: Cd11b Ko Cartilage Presents Increased Lox Expression and Act...mentioning

confidence: 78%

“…Intriguingly, LOX is upregulated in OA cartilage [20], where ECM stiffening occurs in the early stages of OA before its degradation [21]. Moreover, LOX overexpression is associated with increased vascular calcification [22,23].…”

Section: Introductionmentioning

confidence: 99%

CD11b Deficiency Favors Cartilage Calcification via Increased Matrix Vesicles, Apoptosis, and Lysyl Oxidase Activity

Bernabei

Hansen

Ehirchiou

et al. 2023

IJMS

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Pathological cartilage calcification is a hallmark feature of osteoarthritis, a common degenerative joint disease, characterized by cartilage damage, progressively causing pain and loss of movement. The integrin subunit CD11b was shown to play a protective role against cartilage calcification in a mouse model of surgery-induced OA. Here, we investigated the possible mechanism by which CD11b deficiency could favor cartilage calcification by using naïve mice. First, we found by transmission electron microscopy (TEM) that CD11b KO cartilage from young mice presented early calcification spots compared with WT. CD11b KO cartilage from old mice showed progression of calcification areas. Mechanistically, we found more calcification-competent matrix vesicles and more apoptosis in both cartilage and chondrocytes isolated from CD11b-deficient mice. Additionally, the extracellular matrix from cartilage lacking the integrin was dysregulated with increased collagen fibrils with smaller diameters. Moreover, we revealed by TEM that CD11b KO cartilage had increased expression of lysyl oxidase (LOX), the enzyme that catalyzes matrix crosslinks. We confirmed this in murine primary CD11b KO chondrocytes, where Lox gene expression and crosslinking activity were increased. Overall, our results suggest that CD11b integrin regulates cartilage calcification through reduced MV release, apoptosis, LOX activity, and matrix crosslinking. As such, CD11b activation might be a key pathway for maintaining cartilage integrity.

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“…Lysyl oxidase is known to be an enzyme involved in cross-linking collagen. This result claims that collagen metabolism has an important role in the early pathogenesis of calcifications in the arterial walls 15 .…”

Section: The Effect Of Warfarin On Atheromatous Plaque Calcificationsmentioning

confidence: 92%

Warfarin involvement, in comparison to NOACs, in the development of systemic atherosclerosis

Mihăilă¹

2022

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Adverse effects of drugs are one of the objective criteria used for choosing the most appropriate anticoagulant. It is worrying that warfarin may be involved in the progression of systemic atherosclerosis, as more and more articles suggest. Warfarin has been widely used in the past and has greater efficacy compared to dabigatran in patients with mechanical heart valves; there is an antidote to it and it is cheap. Unfortunately, warfarin inhibits the synthesis and activity of Matrix-Gla-Protein, which is the major vitamin K-dependent inhibitor of arterial calcification -an active process associated with atherosclerosis, stimulated by inflammatory mechanisms. Vitamin K antagonizes the NF-κB signaling mechanism and contributes to the prevention of arterial calcifications. Warfarin given in experimental animal models of atherosclerosis contributed to the occurrence of an increased number of aortic calcifications. Warfarin treatment used in clinical trials was associated with the progressive increase of coronary atheroma calcification. Younger patients are more sensitive to warfarin-related arterial calcifications compared to older patients, due to warfarin-induced cellular senescence changes. Non-vitamin K antagonist direct oral anticoagulants do not interact with vitamin K. Edoxaban reduces the inflammatory process in the vascular walls and the proliferation of smooth vascular muscle cells, so it is involved in the prevention of vascular maladaptive remodeling process. Apixaban is able to stabilize the coronary atherosclerotic process. Randomized clinical trials are needed to evaluate the impact of warfarin on plaque stability and cardiovascular evolution of patients.

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Inhibition of extracellular matrix integrity attenuates the early phase of aortic medial calcification in a rodent model

Cited by 15 publications

References 48 publications

Identification of potential biomarkers of vascular calcification using bioinformatics analysis and validation in vivo

Identification of potential biomarkers of vascular calcification using bioinformatics analysis and validation in vivo

CD11b Deficiency Favors Cartilage Calcification via Increased Matrix Vesicles, Apoptosis, and Lysyl Oxidase Activity

Warfarin involvement, in comparison to NOACs, in the development of systemic atherosclerosis

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