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1.
Int J Mol Sci ; 25(11)2024 May 24.
Article de Anglais | MEDLINE | ID: mdl-38891922

RÉSUMÉ

Vascular calcification has a global health impact that is closely linked to bone loss. The Receptor Activator of Nuclear Factor Kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, fundamental for bone metabolism, also plays an important role in vascular calcification. The Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), a novel receptor for RANKL, regulates bone remodeling, and it appears to be involved in vascular calcification. Besides RANKL, LGR4 interacts with R-spondins (RSPOs), which are known for their roles in bone but are less understood in vascular calcification. Studies were conducted in rats with chronic renal failure fed normal or high phosphorus diets for 18 weeks, with and without control of circulating parathormone (PTH) levels, resulting in different degrees of aortic calcification. Additionally, vascular smooth muscle cells (VSMCs) were cultured under non-calcifying (1 mM phosphate) and calcifying (3 mM phosphate) media with different concentrations of PTH. To explore the role of RANKL in VSMC calcification, increasing concentrations of soluble RANKL were added to non-calcifying and calcifying media. The effects mediated by RANKL binding to its receptor LGR4 were investigated by silencing the LGR4 receptor in VSMCs. Furthermore, the gene expression of the RANK/RANKL/OPG system and the ligands of LGR4 was assessed in human epigastric arteries obtained from kidney transplant recipients with calcification scores (Kauppila Index). Increased aortic calcium in rats coincided with elevated systolic blood pressure, upregulated Lgr4 and Rankl gene expression, downregulated Opg gene expression, and higher serum RANKL/OPG ratio without changes in Rspos gene expression. Elevated phosphate in vitro increased calcium content and expression of Rankl and Lgr4 while reducing Opg. Elevated PTH in the presence of high phosphate exacerbated the increase in calcium content. No changes in Rspos were observed under the conditions employed. The addition of soluble RANKL to VSMCs induced genotypic differentiation and calcification, partly prevented by LGR4 silencing. In the epigastric arteries of individuals presenting vascular calcification, the gene expression of RANKL was higher. While RSPOs show minimal impact on VSMC calcification, RANKL, interacting with LGR4, drives osteogenic differentiation in VSMCs, unveiling a novel mechanism beyond RANKL-RANK binding.


Sujet(s)
Muscles lisses vasculaires , Ligand de RANK , Récepteurs couplés aux protéines G , Calcification vasculaire , Ligand de RANK/métabolisme , Ligand de RANK/génétique , Animaux , Récepteurs couplés aux protéines G/métabolisme , Récepteurs couplés aux protéines G/génétique , Calcification vasculaire/métabolisme , Calcification vasculaire/anatomopathologie , Muscles lisses vasculaires/métabolisme , Muscles lisses vasculaires/anatomopathologie , Rats , Humains , Mâle , Myocytes du muscle lisse/métabolisme , Myocytes du muscle lisse/anatomopathologie , Ostéoprotégérine/métabolisme , Ostéoprotégérine/génétique , Hormone parathyroïdienne/métabolisme , Cellules cultivées , Rat Sprague-Dawley
2.
Front Immunol ; 15: 1395596, 2024.
Article de Anglais | MEDLINE | ID: mdl-38919629

RÉSUMÉ

Vascular calcification (VC) is considered a common pathological process in various vascular diseases. Accumulating studies have confirmed that VC is involved in the inflammatory response in heart disease, and SPP1+ macrophages play an important role in this process. In VC, studies have focused on the physiological and pathological functions of macrophages, such as pro-inflammatory or anti-inflammatory cytokines and pro-fibrotic vesicles. Additionally, macrophages and activated lymphocytes highly express SPP1 in atherosclerotic plaques, which promote the formation of fatty streaks and plaque development, and SPP1 is also involved in the calcification process of atherosclerotic plaques that results in heart failure, but the crosstalk between SPP1-mediated immune cells and VC has not been adequately addressed. In this review, we summarize the regulatory effect of SPP1 on VC in T cells, macrophages, and dendritic cells in different organs' VC, which could be a potential therapeutic target for VC.


Sujet(s)
Macrophages , Ostéopontine , Calcification vasculaire , Humains , Ostéopontine/métabolisme , Calcification vasculaire/immunologie , Calcification vasculaire/métabolisme , Calcification vasculaire/anatomopathologie , Animaux , Macrophages/immunologie , Macrophages/métabolisme , Cellules dendritiques/immunologie , Cellules dendritiques/métabolisme , Lymphocytes T/immunologie , Lymphocytes T/métabolisme , Plaque d'athérosclérose/immunologie , Plaque d'athérosclérose/anatomopathologie , Plaque d'athérosclérose/métabolisme
3.
Nat Commun ; 15(1): 4985, 2024 Jun 11.
Article de Anglais | MEDLINE | ID: mdl-38862515

RÉSUMÉ

Hyperglycemia accelerates calcification of atherosclerotic plaques in diabetic patients, and the accumulation of advanced glycation end products (AGEs) is closely related to the atherosclerotic calcification. Here, we show that hyperglycemia-mediated AGEs markedly increase vascular smooth muscle cells (VSMCs) NF90/110 activation in male diabetic patients with atherosclerotic calcified samples. VSMC-specific NF90/110 knockout in male mice decreases obviously AGEs-induced atherosclerotic calcification, along with the inhibitions of VSMC phenotypic changes to osteoblast-like cells, apoptosis, and matrix vesicle release. Mechanistically, AGEs increase the activity of NF90, which then enhances ubiquitination and degradation of AGE receptor 1 (AGER1) by stabilizing the mRNA of E3 ubiquitin ligase FBXW7, thus causing the accumulation of more AGEs and atherosclerotic calcification. Collectively, our study demonstrates the effects of VSMC NF90 in mediating the metabolic imbalance of AGEs to accelerate diabetic atherosclerotic calcification. Therefore, inhibition of VSMC NF90 may be a potential therapeutic target for diabetic atherosclerotic calcification.


Sujet(s)
Athérosclérose , Protéine-7 contenant une boite F et des répétitions WD , Produits terminaux de glycation avancée , Souris knockout , Muscles lisses vasculaires , Myocytes du muscle lisse , Facteurs nucléaires-90 , Récepteur spécifique des produits finaux de glycosylation avancée , Animaux , Mâle , Souris , Produits terminaux de glycation avancée/métabolisme , Muscles lisses vasculaires/métabolisme , Muscles lisses vasculaires/anatomopathologie , Athérosclérose/métabolisme , Athérosclérose/génétique , Athérosclérose/anatomopathologie , Humains , Protéine-7 contenant une boite F et des répétitions WD/métabolisme , Protéine-7 contenant une boite F et des répétitions WD/génétique , Myocytes du muscle lisse/métabolisme , Myocytes du muscle lisse/anatomopathologie , Facteurs nucléaires-90/métabolisme , Facteurs nucléaires-90/génétique , Récepteur spécifique des produits finaux de glycosylation avancée/métabolisme , Récepteur spécifique des produits finaux de glycosylation avancée/génétique , Calcification vasculaire/métabolisme , Calcification vasculaire/anatomopathologie , Calcification vasculaire/génétique , Souris de lignée C57BL , Ubiquitination , Diabète expérimental/métabolisme , Diabète expérimental/complications , Diabète expérimental/génétique , Diabète expérimental/anatomopathologie , Hyperglycémie/métabolisme , Hyperglycémie/génétique , Plaque d'athérosclérose/métabolisme , Plaque d'athérosclérose/anatomopathologie , Plaque d'athérosclérose/génétique , Apoptose
4.
Gut Microbes ; 16(1): 2351532, 2024.
Article de Anglais | MEDLINE | ID: mdl-38727248

RÉSUMÉ

Emerging evidence indicates that alteration of gut microbiota plays an important role in chronic kidney disease (CKD)-related vascular calcification (VC). We aimed to investigate the specific gut microbiota and the underlying mechanism involved in CKD-VC. We identified an increased abundance of Prevotella copri (P. copri) in the feces of CKD rats (induced by using 5/6 nephrectomy followed by a high calcium and phosphate diet) with aortic calcification via amplicon sequencing of 16S rRNA genes. In patients with CKD, we further confirmed a positive correlation between abundance of P. copri and aortic calcification scores. Moreover, oral administration of live P. copri aggravated CKD-related VC and osteogenic differentiation of vascular smooth muscle cells in vivo, accompanied by intestinal destruction, enhanced expression of Toll-like receptor-4 (TLR4), and elevated lipopolysaccharide (LPS) levels. In vitro and ex vivo experiments consistently demonstrated that P. copri-derived LPS (Pc-LPS) accelerated high phosphate-induced VC and VSMC osteogenic differentiation. Mechanistically, Pc-LPS bound to TLR4, then activated the nuclear factor κB (NF-κB) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome signals during VC. Inhibition of NF-κB reduced NLRP3 inflammasome and attenuated Pc-LPS-induced VSMC calcification. Our study clarifies a novel role of P. copri in CKD-related VC, by the mechanisms involving increased inflammation-regulating metabolites including Pc-LPS, and activation of the NF-κB/NLRP3 signaling pathway. These findings highlight P. copri and its-derived LPS as potential therapeutic targets for VC in CKD.


Sujet(s)
Microbiome gastro-intestinal , Lipopolysaccharides , Facteur de transcription NF-kappa B , Prevotella , Transduction du signal , Calcification vasculaire , Animaux , Humains , Mâle , Rats , Fèces/microbiologie , Inflammasomes/métabolisme , Lipopolysaccharides/métabolisme , Muscles lisses vasculaires/métabolisme , Muscles lisses vasculaires/anatomopathologie , Myocytes du muscle lisse/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Protéine-3 de la famille des NLR contenant un domaine pyrine/métabolisme , Protéine-3 de la famille des NLR contenant un domaine pyrine/génétique , Ostéogenèse/effets des médicaments et des substances chimiques , Prevotella/métabolisme , Rat Sprague-Dawley , Insuffisance rénale chronique/complications , Insuffisance rénale chronique/microbiologie , Insuffisance rénale chronique/anatomopathologie , Récepteur de type Toll-4/métabolisme , Récepteur de type Toll-4/génétique , Calcification vasculaire/métabolisme , Calcification vasculaire/microbiologie , Calcification vasculaire/anatomopathologie
5.
Cells ; 13(9)2024 Apr 26.
Article de Anglais | MEDLINE | ID: mdl-38727287

RÉSUMÉ

Currently, more and more people are suffering from chronic kidney disease (CKD). It is estimated that CKD affects over 10% of the population worldwide. This is a significant issue, as the kidneys largely contribute to maintaining homeostasis by, among other things, regulating blood pressure, the pH of blood, and the water-electrolyte balance and by eliminating unnecessary metabolic waste products from blood. What is more, this disease does not show any specific symptoms at the beginning. The development of CKD is predisposed by certain conditions, such as diabetes mellitus or hypertension. However, these disorders are not the only factors promoting the onset and progression of CKD. The primary purpose of this review is to examine renin-angiotensin-aldosterone system (RAAS) activity, transforming growth factor-ß1 (TGF-ß1), vascular calcification (VC), uremic toxins, and hypertension in the context of their impact on the occurrence and the course of CKD. We firmly believe that a deeper comprehension of the cellular and molecular mechanisms underlying CKD can lead to an enhanced understanding of the disease. In the future, this may result in the development of medications targeting specific mechanisms involved in the decline of kidney function. Our paper unveils the selected processes responsible for the deterioration of renal filtration abilities.


Sujet(s)
Évolution de la maladie , Insuffisance rénale chronique , Système rénine-angiotensine , Humains , Insuffisance rénale chronique/anatomopathologie , Insuffisance rénale chronique/métabolisme , Système rénine-angiotensine/physiologie , Animaux , Hypertension artérielle/physiopathologie , Hypertension artérielle/anatomopathologie , Calcification vasculaire/métabolisme , Calcification vasculaire/anatomopathologie , Calcification vasculaire/physiopathologie , Facteur de croissance transformant bêta-1/métabolisme , Rein/anatomopathologie , Rein/métabolisme , Rein/physiopathologie
6.
Article de Anglais | MEDLINE | ID: mdl-38780291

RÉSUMÉ

ABSTRACT: Vascular calcification (VC), a major complication in chronic kidney disease (CKD), is predominantly driven by osteoblastic differentiation. Recent studies have highlighted the crucial role of microRNAs in CKD's pathogenesis. Here, our research focused on the effects of miR-204-5p and its molecular mechanisms within VC. We initially found a notable decrease in miR-204-5p levels in human aortic vascular smooth muscle cells stimulated with inorganic phosphate, using this as a VC model in vitro. Following the overexpression of miR-204-5p, a decrease in VC was observed, as indicated by alizarin red S staining and measurements of calcium content. This decrease was accompanied by lower levels of the osteogenic marker, runt-related transcription factor 2, and higher levels of α-smooth muscle actin, a marker of contractility. Further investigation showed that calcium/calmodulin-dependent protein kinase 1 (CAMK1), which is a predicted target of miR-204-5p, promotes VC. Conversely, overexpressing miR-204-5p reduced VC by suppressing CAMK1 activity. Overexpressing miR-204-5p also effectively mitigated aortic calcification in an in vivo rat model. In summary, our research indicated that targeting the miR-204-5p/CAMK1 pathway could be a viable strategy for mitigating VC in CKD patients.


Sujet(s)
Différenciation cellulaire , microARN , Muscles lisses vasculaires , Ostéogenèse , Calcification vasculaire , microARN/génétique , microARN/métabolisme , Humains , Calcification vasculaire/génétique , Calcification vasculaire/métabolisme , Calcification vasculaire/anatomopathologie , Muscles lisses vasculaires/métabolisme , Muscles lisses vasculaires/anatomopathologie , Ostéogenèse/génétique , Animaux , Rats , Aorte/anatomopathologie , Myocytes du muscle lisse/métabolisme , Mâle , Cellules cultivées , Rat Sprague-Dawley
7.
Redox Biol ; 73: 103183, 2024 Jul.
Article de Anglais | MEDLINE | ID: mdl-38759418

RÉSUMÉ

AIMS: Vascular calcification is strongly linked to the development of major adverse cardiovascular events, but effective treatments are lacking. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an emerging category of oral hypoglycemic drugs that have displayed marked effects on metabolic and cardiovascular diseases, including recently reported vascular medial calcification. However, the roles and underlying mechanisms of SGLT2 inhibitors in vascular calcification have not been fully elucidated. Thus, we aimed to further determine whether SGLT2 inhibitors protect against vascular calcification and to investigate the mechanisms involved. METHODS AND RESULTS: A computed tomography angiography investigation of coronary arteries from 1554 patients with type 2 diabetes revealed that SGLT2 inhibitor use was correlated with a lower Agatston calcification score. In the vitamin D3 overdose, 5/6 nephrectomy chronic kidney disease-induced medial calcification and Western diet-induced atherosclerotic intimal calcification models, dapagliflozin (DAPA) substantially alleviated vascular calcification in the aorta. Furthermore, we showed that DAPA reduced vascular calcification via Runx2-dependent osteogenic transdifferentiation in vascular smooth muscle cells (VSMCs). Transcriptome profiling revealed that thioredoxin domain containing 5 (TXNDC5) was involved in the attenuation of vascular calcification by DAPA. Rescue experiments showed that DAPA-induced TXNDC5 downregulation in VSMCs blocked the protective effect on vascular calcification. Furthermore, TXNDC5 downregulation disrupted protein folding-dependent Runx2 stability and promoted subsequent proteasomal degradation. Moreover, DAPA downregulated TXNDC5 expression via amelioration of oxidative stress and ATF6-dependent endoplasmic reticulum stress. Consistently, the class effects of SGLT2 inhibitors on vascular calcification were validated with empagliflozin in intimal and medial calcification models. CONCLUSIONS: SGLT2 inhibitors ameliorate vascular calcification through blocking endoplasmic reticulum stress-dependent TXNDC5 upregulation and promoting subsequent Runx2 proteasomal degradation, suggesting that SGLT2 inhibitors are potentially beneficial for vascular calcification treatment and prevention.


Sujet(s)
Glucosides , Ostéogenèse , Inhibiteurs du cotransporteur sodium-glucose de type 2 , Calcification vasculaire , Calcification vasculaire/métabolisme , Calcification vasculaire/traitement médicamenteux , Calcification vasculaire/anatomopathologie , Calcification vasculaire/étiologie , Inhibiteurs du cotransporteur sodium-glucose de type 2/pharmacologie , Animaux , Humains , Ostéogenèse/effets des médicaments et des substances chimiques , Souris , Glucosides/pharmacologie , Mâle , Thiorédoxines/métabolisme , Thiorédoxines/génétique , Composés benzhydryliques/pharmacologie , Diabète de type 2/métabolisme , Diabète de type 2/complications , Diabète de type 2/traitement médicamenteux , Réticulum endoplasmique/métabolisme , Réticulum endoplasmique/effets des médicaments et des substances chimiques , Rats , Sous-unité alpha 1 du facteur CBF/métabolisme , Sous-unité alpha 1 du facteur CBF/génétique , Modèles animaux de maladie humaine , Muscles lisses vasculaires/métabolisme , Muscles lisses vasculaires/effets des médicaments et des substances chimiques , Muscles lisses vasculaires/anatomopathologie , Muscles lisses vasculaires/cytologie , Myocytes du muscle lisse/métabolisme , Myocytes du muscle lisse/effets des médicaments et des substances chimiques , Stress du réticulum endoplasmique/effets des médicaments et des substances chimiques , Femelle
8.
Cardiovasc Diabetol ; 23(1): 186, 2024 May 29.
Article de Anglais | MEDLINE | ID: mdl-38812011

RÉSUMÉ

BACKGROUND: Vascular calcification (VC) is an independent risk factor for cardiovascular diseases. Recently, ferroptosis has been recognised as a novel therapeutic target for cardiovascular diseases. Although an association between ferroptosis and vascular calcification has been reported, the role and mechanism of iron overload in vascular calcification are still poorly understood. Specifically, further in-depth research is required on whether metalloproteins SLC39a14 and SLC39a8 are involved in ferroptosis induced by iron overload. METHODS: R language was employed for the differential analysis of the dataset, revealing the correlation between ferroptosis and calcification. The experimental approaches encompassed both in vitro and in vivo studies, incorporating the use of iron chelators and models of iron overload. Additionally, gain- and loss-of-function experiments were conducted to investigate iron's effects on vascular calcification comprehensively. Electron microscopy, immunofluorescence, western blotting, and real-time polymerase chain reaction were used to elucidate how Slc39a14 and Slc39a8 mediate iron overload and promote calcification. RESULTS: Ferroptosis was observed in conjunction with vascular calcification (VC); the association was consistently confirmed by in vitro and in vivo studies. Our results showed a positive correlation between iron overload in VSMCs and calcification. Iron chelators are effective in reversing VC and iron overload exacerbates this process. The expression levels of the metal transport proteins Slc39a14 and Slc39a8 were significantly upregulated during calcification; the inhibition of their expression alleviated VC. Conversely, Slc39a14 overexpression exacerbates calcification and promotes intracellular iron accumulation in VSMCs. CONCLUSIONS: Our research demonstrates that iron overload occurs during VC, and that inhibition of Slc39a14 and Slc39a8 significantly relieves VC by intercepting iron overload-induced ferroptosis in VSMCs, providing new insights into the VC treatment.


Sujet(s)
Transporteurs de cations , Modèles animaux de maladie humaine , Ferroptose , Agents chélateurs du fer , Souris de lignée C57BL , Muscles lisses vasculaires , Myocytes du muscle lisse , Calcification vasculaire , Ferroptose/effets des médicaments et des substances chimiques , Calcification vasculaire/métabolisme , Calcification vasculaire/anatomopathologie , Animaux , Transporteurs de cations/métabolisme , Transporteurs de cations/génétique , Myocytes du muscle lisse/métabolisme , Myocytes du muscle lisse/effets des médicaments et des substances chimiques , Myocytes du muscle lisse/anatomopathologie , Muscles lisses vasculaires/anatomopathologie , Muscles lisses vasculaires/métabolisme , Muscles lisses vasculaires/effets des médicaments et des substances chimiques , Agents chélateurs du fer/pharmacologie , Agents chélateurs du fer/usage thérapeutique , Transduction du signal , Mâle , Humains , Fer/métabolisme , Surcharge en fer/métabolisme , Surcharge en fer/anatomopathologie
9.
Vascul Pharmacol ; 155: 107376, 2024 Jun.
Article de Anglais | MEDLINE | ID: mdl-38692418

RÉSUMÉ

Cardiovascular disease and osteoporosis, major causes of morbidity and mortality, are associated with hyperlipidemia. Recent studies show that empagliflozin (EMPA), an inhibitor of sodium-glucose cotransporter-2 (SGLT2), improves cardiovascular health. In preclinical animal studies, EMPA mitigates vascular calcification in the males but its effects in the females are not known. Thus, we used female mice to test the effects of EMPA on calcification in the artery wall, cardiac function, and skeletal bone. By serial in vivo microCT imaging, we followed the progression of aortic calcification and bone mineral density in young and older female Apoe-/- mice fed a high-fat diet with or without EMPA. The two different age groups were used to compare early vs. advanced stages of aortic calcification. Results show that EMPA treatment increased urine glucose levels. Aortic calcium content increased in both the controls and the EMPA-treated mice, and EMPA did not affect progression of aortic calcium content in both young and older mice. However, 3-D segmentation analysis of aortic calcium deposits on microCT images revealed that EMPA-treated mice had significantly less surface area and volume of calcified deposits as well as fewer numbers of deposits than the control mice. To test for direct effects on vascular cell calcification, we treated murine aortic smooth muscle cells with EMPA, and results showed a slight inhibition of alkaline phosphatase activity and inflammatory matrix calcification. As for skeletal bone, EMPA-treated mice had significantly lower BMD than the controls in both the lumbar vertebrae and femoral bones in both young and older mice. The findings suggest that, in hyperlipidemic female mice, unlike males, SGLT2 inhibition with empagliflozin does not mitigate progression of aortic calcification and may even lower skeletal bone density.


Sujet(s)
Composés benzhydryliques , Densité osseuse , Modèles animaux de maladie humaine , Glucosides , Hyperlipidémies , Souris invalidées pour les gènes ApoE , Inhibiteurs du cotransporteur sodium-glucose de type 2 , Calcification vasculaire , Microtomographie aux rayons X , Animaux , Glucosides/pharmacologie , Composés benzhydryliques/pharmacologie , Femelle , Inhibiteurs du cotransporteur sodium-glucose de type 2/pharmacologie , Calcification vasculaire/anatomopathologie , Calcification vasculaire/traitement médicamenteux , Calcification vasculaire/prévention et contrôle , Calcification vasculaire/métabolisme , Hyperlipidémies/traitement médicamenteux , Densité osseuse/effets des médicaments et des substances chimiques , Aorte/effets des médicaments et des substances chimiques , Aorte/anatomopathologie , Aorte/métabolisme , Aorte/imagerie diagnostique , Aorte/physiopathologie , Maladies de l'aorte/anatomopathologie , Maladies de l'aorte/métabolisme , Maladies de l'aorte/prévention et contrôle , Maladies de l'aorte/traitement médicamenteux , Maladies de l'aorte/physiopathologie , Maladies de l'aorte/imagerie diagnostique , Souris de lignée C57BL , Alimentation riche en graisse , Souris , Facteurs âges , Cellules cultivées
10.
Cell Signal ; 120: 111211, 2024 Aug.
Article de Anglais | MEDLINE | ID: mdl-38705504

RÉSUMÉ

Vascular calcification (VC) is a characteristic feature in patients with diabetes mellitus (DM) and is closely associated with the osteogenic differentiation of vascular smooth muscle cells (VSMCs). Ubiquitin-Specific Protease 10 (USP10) has been shown to regulate multiple cellular processes; however, its relationship with diabetic VC remains unclear. This study aims to elucidate the role of USP10 in VC development and the underlying regulatory mechanisms. Nε-carboxymethyl lysine (CML) was significantly increased in calcified ateries from diabetic atherosclerosis ApoE-/- mice fed with high-fat diets. CML downregulated USP10 expression in VSMCs and calcified mice coronary arteries, as assessd by Western blotting, RT-qPCR,immunofluorescence and immunohistochemistry. Loss-and gain-of-function experiments were conducted both in vitro and in vivo to verify the biological functions of USP10. Ectopic expression of USP10 mitigated the severity of VC. With regard to the mechanism, the interaction between USP10 and AMPKα was investigated through double-label immunofluorescence and Co-immunoprecipitation. In vitro ubiquitination assay revealed that USP10 was capable of mediating AMPKα ubiquitination and caused increased AMPKα phosphorylation level at Thr172. Moreover, the anticalcification effect of USP10 was reversed by pharmacological inhibition of AMPK signaling pathway. The current fundings suggest an important role of USP10 in diabetic VC progression, at least in part, via mediating the ubiquitination and activation of AMPKα. USP10 may serve as a novel therapeutic target for the treatment of diabetic VC.


Sujet(s)
AMP-Activated Protein Kinases , Athérosclérose , Lysine , Ubiquitin thiolesterase , Calcification vasculaire , Animaux , Ubiquitin thiolesterase/métabolisme , Ubiquitin thiolesterase/génétique , Calcification vasculaire/métabolisme , Calcification vasculaire/anatomopathologie , Souris , Athérosclérose/métabolisme , Athérosclérose/anatomopathologie , Lysine/métabolisme , Lysine/analogues et dérivés , AMP-Activated Protein Kinases/métabolisme , Mâle , Ubiquitination , Souris de lignée C57BL , Humains , Muscles lisses vasculaires/métabolisme , Muscles lisses vasculaires/anatomopathologie , Myocytes du muscle lisse/métabolisme , Myocytes du muscle lisse/anatomopathologie , Diabète expérimental/métabolisme , Diabète expérimental/complications , Diabète expérimental/anatomopathologie
11.
Am J Physiol Cell Physiol ; 326(6): C1721-C1734, 2024 Jun 01.
Article de Anglais | MEDLINE | ID: mdl-38646788

RÉSUMÉ

Atherosclerosis (AS) is a significant contributor to cardio-cerebrovascular ischemia diseases, resulting in high mortality rates worldwide. During AS, vascular smooth muscle cells (VSMCs) play a crucial role in plaque formation by undergoing phenotypic and osteogenic switching. Long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has previously been identified as a nuclear regulator that promotes tumorigenesis and metastasis, but its role in regulating VSMCs in AS remains unclear. Our study aimed to investigate the biological functions and specific mechanisms of NEAT1 in regulating VSMCs in AS. We found that NEAT1 was upregulated in the aortas of AS mouse models and dedifferentiated primary VSMCs. Silencing NEAT1 in vitro attenuated the proliferation, migration, and osteogenic differentiation of VSMCs, while NEAT1 overexpression had the opposite effect. Furthermore, NEAT1 promoted VSMC osteogenic differentiation and vascular calcification in both in vivo and in vitro vascular calcification models. We also discovered that NEAT1 directly activates enhancer of zeste homolog 2 (EZH2), an epigenetic enzyme that suppresses the expression of senescence- and antimigration-related genes, by translocating it into the nucleus. CUT&Tag assay revealed that NEAT1 guides EZH2 to the promoters of senescence-related genes (P16, P21, and TIMP3), methylating local histones to reduce their transcription. Our findings suggest that NEAT1 functions in AS by modulating the epigenetic function of EZH2, which enhances the proliferation, migration, and osteogenic differentiation of VSMCs. This study provides new insights into the molecular mechanisms underlying the pathogenesis of AS and highlights the potential of NEAT1 as a therapeutic target of AS.NEW & NOTEWORTHY Our study demonstrates that the upregulation of long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) promotes proliferation and migration during phenotypic switching of vascular smooth muscle cells in atherosclerosis. We also provide in vivo and in vitro evidence that NEAT1 accelerates vascular calcification. Our findings identified the direct interaction between enhancer of zeste homolog 2 (EZH2) and NEAT1 during atherosclerosis. NEAT1 is necessary for EZH2 to translocate from the cytoplasm to the nucleus, where EZH2 epigenetically inhibits the expression of genes related to senescence and antimigration.


Sujet(s)
Athérosclérose , Différenciation cellulaire , Protéine-2 homologue de l'activateur de Zeste , Muscles lisses vasculaires , Myocytes du muscle lisse , Ostéogenèse , ARN long non codant , Calcification vasculaire , ARN long non codant/génétique , ARN long non codant/métabolisme , Protéine-2 homologue de l'activateur de Zeste/métabolisme , Protéine-2 homologue de l'activateur de Zeste/génétique , Animaux , Muscles lisses vasculaires/métabolisme , Muscles lisses vasculaires/anatomopathologie , Ostéogenèse/génétique , Athérosclérose/génétique , Athérosclérose/anatomopathologie , Athérosclérose/métabolisme , Myocytes du muscle lisse/métabolisme , Myocytes du muscle lisse/anatomopathologie , Calcification vasculaire/anatomopathologie , Calcification vasculaire/génétique , Calcification vasculaire/métabolisme , Souris , Mâle , Souris de lignée C57BL , Prolifération cellulaire , Phénotype , Cellules cultivées , Humains , Mouvement cellulaire
12.
Cardiovasc Res ; 120(7): 699-707, 2024 May 29.
Article de Anglais | MEDLINE | ID: mdl-38636937

RÉSUMÉ

Despite the air quality has been generally improved in recent years, ambient fine particulate matter (PM2.5), a major contributor to air pollution, remains one of the major threats to public health. Vascular calcification is a systematic pathology associated with an increased risk of cardiovascular disease. Although the epidemiological evidence has uncovered the association between PM2.5 exposure and vascular calcification, little is known about the underlying mechanisms. The adverse outcome pathway (AOP) concept offers a comprehensive interpretation of all of the findings obtained by toxicological and epidemiological studies. In this review, reactive oxygen species generation was identified as the molecular initiating event (MIE), which targeted subsequent key events (KEs) such as oxidative stress, inflammation, endoplasmic reticulum stress, and autophagy, from the cellular to the tissue/organ level. These KEs eventually led to the adverse outcome, namely increased incidence of vascular calcification and atherosclerosis morbidity. To the best of our knowledge, this is the first AOP framework devoted to PM2.5-associated vascular calcification, which benefits future investigations by identifying current limitations and latent biomarkers.


Sujet(s)
Polluants atmosphériques , Stress oxydatif , Matière particulaire , Calcification vasculaire , Matière particulaire/effets indésirables , Humains , Calcification vasculaire/métabolisme , Calcification vasculaire/épidémiologie , Calcification vasculaire/anatomopathologie , Calcification vasculaire/induit chimiquement , Animaux , Polluants atmosphériques/effets indésirables , Stress oxydatif/effets des médicaments et des substances chimiques , Facteurs de risque , Appréciation des risques , Maladies cardiovasculaires/épidémiologie , Maladies cardiovasculaires/métabolisme , Espèces réactives de l'oxygène/métabolisme , Exposition environnementale/effets indésirables , Pollution de l'air/effets indésirables , Autophagie/effets des médicaments et des substances chimiques , Médiateurs de l'inflammation/métabolisme , Taille de particule , Pronostic , Stress du réticulum endoplasmique/effets des médicaments et des substances chimiques , Transduction du signal
13.
Atherosclerosis ; 392: 117527, 2024 May.
Article de Anglais | MEDLINE | ID: mdl-38583286

RÉSUMÉ

BACKGROUND AND AIMS: Diabetic atherosclerotic vascular disease is characterized by extensive vascular calcification. However, an elevated blood glucose level alone does not explain this pathogenesis. We investigated the metabolic markers underlying diabetic atherosclerosis and whether extracellular Hsp90α (eHsp90α) triggers vascular endothelial calcification in this particular metabolic environment. METHODS: A parallel human/animal model metabolomics approach was used. We analyzed 40 serum samples collected from 24 patients with atherosclerosis and from the STZ-induced ApoE-/- mouse model. A multivariate statistical analysis of the data was performed, and mouse aortic tissue was collected for the assessment of plaque formation. In vitro, the effects of eHsp90α on endothelial cell calcification were assessed by serum analysis, Western blotting and immunoelectron microscopy. RESULTS: Diabetic ApoE-/- mice showed more severe plaque lesions and calcification damage. Stearamide, oleamide, l-thyroxine, l-homocitrulline and l-citrulline are biomarkers of diabetic ASVD; l-thyroxine was downregulated in both groups, and the thyroid sensitivity index was correlated with serum Hsp90α concentration. In vitro studies showed that eHsp90α increased Runx2 expression in endothelial cells through the LRP1 receptor. l-thyroxine reduced the increase in Runx2 levels caused by eHsp90α and affected the distribution and expression of LRP1 through hydrogen bonding with glutamine at position 1054 in the extracellular segment of LRP1. CONCLUSIONS: This study provides a mechanistic link between characteristic serum metabolites and diabetic atherosclerosis and thus offers new insight into the role of extracellular Hsp90α in promoting vascular calcification.


Sujet(s)
Diabète expérimental , Protéines du choc thermique HSP90 , Souris invalidées pour les gènes ApoE , Plaque d'athérosclérose , Thyroxine , Calcification vasculaire , Humains , Animaux , Protéines du choc thermique HSP90/métabolisme , Calcification vasculaire/métabolisme , Calcification vasculaire/anatomopathologie , Mâle , Diabète expérimental/traitement médicamenteux , Diabète expérimental/complications , Thyroxine/sang , Femelle , Protéine-1 apparentée au récepteur des LDL/métabolisme , Adulte d'âge moyen , Sous-unité alpha 1 du facteur CBF/métabolisme , Souris , Athérosclérose/métabolisme , Athérosclérose/anatomopathologie , Angiopathies diabétiques/métabolisme , Angiopathies diabétiques/anatomopathologie , Angiopathies diabétiques/étiologie , Métabolomique/méthodes , Cellules endothéliales/métabolisme , Cellules endothéliales/effets des médicaments et des substances chimiques , Métabolome/effets des médicaments et des substances chimiques , Sujet âgé , Souris de lignée C57BL , Maladies de l'aorte/métabolisme , Maladies de l'aorte/anatomopathologie , Maladies de l'aorte/sang , Marqueurs biologiques/sang , Cellules endothéliales de la veine ombilicale humaine/métabolisme
14.
Circ Res ; 134(11): 1427-1447, 2024 May 24.
Article de Anglais | MEDLINE | ID: mdl-38629274

RÉSUMÉ

BACKGROUND: Medial arterial calcification is a chronic systemic vascular disorder distinct from atherosclerosis and is commonly observed in patients with chronic kidney disease, diabetes, and aging individuals. We previously showed that NR4A3 (nuclear receptor subfamily 4 group A member 3), an orphan nuclear receptor, is a key regulator in apo (apolipoprotein) A-IV-induced atherosclerosis progression; however, its role in vascular calcification is poorly understood. METHODS: We generated NR4A3-/- mice and 2 different types of medial arterial calcification models to investigate the biological roles of NR4A3 in vascular calcification. RNA-seq was performed to determine the transcriptional profile of NR4A3-/- vascular smooth muscle cells under ß-glycerophosphate treatment. We integrated Cleavage Under Targets and Tagmentation analysis and RNA-seq data to further investigate the gene regulatory mechanisms of NR4A3 in arterial calcification and target genes regulated by histone lactylation. RESULTS: NR4A3 expression was upregulated in calcified aortic tissues from chronic kidney disease mice, 1,25(OH)2VitD3 overload-induced mice, and human calcified aorta. NR4A3 deficiency preserved the vascular smooth muscle cell contractile phenotype, inhibited osteoblast differentiation-related gene expression, and reduced calcium deposition in the vasculature. Further, NR4A3 deficiency lowered the glycolytic rate and lactate production during the calcification process and decreased histone lactylation. Mechanistic studies further showed that NR4A3 enhanced glycolysis activity by directly binding to the promoter regions of the 2 glycolysis genes ALDOA and PFKL and driving their transcriptional initiation. Furthermore, histone lactylation promoted medial calcification both in vivo and in vitro. NR4A3 deficiency inhibited the transcription activation and expression of Phospho1 (phosphatase orphan 1). Consistently, pharmacological inhibition of Phospho1 attenuated calcium deposition in NR4A3-overexpressed vascular smooth muscle cells, whereas overexpression of Phospho1 reversed the anticalcific effect of NR4A3 deficiency in vascular smooth muscle cells. CONCLUSIONS: Taken together, our findings reveal that NR4A3-mediated histone lactylation is a novel metabolome-epigenome signaling cascade mechanism that participates in the pathogenesis of medial arterial calcification.


Sujet(s)
Histone , Souris de lignée C57BL , Souris knockout , Muscles lisses vasculaires , Membre-3 du groupe A de la sous-famille-4 de récepteurs nucléaires , Calcification vasculaire , Animaux , Calcification vasculaire/métabolisme , Calcification vasculaire/génétique , Calcification vasculaire/anatomopathologie , Souris , Humains , Histone/métabolisme , Muscles lisses vasculaires/métabolisme , Muscles lisses vasculaires/anatomopathologie , Membre-3 du groupe A de la sous-famille-4 de récepteurs nucléaires/métabolisme , Membre-3 du groupe A de la sous-famille-4 de récepteurs nucléaires/génétique , Mâle , Myocytes du muscle lisse/métabolisme , Myocytes du muscle lisse/anatomopathologie , Cellules cultivées , Protéines de liaison à l'ADN , Protéines de tissu nerveux , Récepteurs aux stéroïdes , Récepteurs des hormones thyroïdiennes
16.
Exp Cell Res ; 438(1): 114031, 2024 May 01.
Article de Anglais | MEDLINE | ID: mdl-38616032

RÉSUMÉ

Diabetes is closely associated with vascular calcification (VC). Exorbitant glucose concentration activates pro-calcific effects in vascular smooth muscle cells (VSMCs). This study enrolled 159 elderly patients with type 2 diabetes and divided them into three groups, T1, T2 and T3, according to brachial-ankle pulse wave velocity(BaPWV). There were statistically significant differences in the waist circumference, waist hip ratio, systolic blood pressure, 12,13-diHOME (a lipokin) concentration among T1, T2 and T3. 12,13-diHOME levels were positively correlated to high density lipoprotein cholesterol and total cholesterol, but negatively correlated to with waist circumference, waist hip ratio, systolic blood pressure and baPWV. Studies in vitro showed that 12,13-diHOME effectively inhibits calcification in VSMCs under high glucose conditions. Notably, 12,13-diHOME suppressed the up-regulation of carnitine O-palmitoyltransferase 1 (CPT1A) and CPT1A-induced succinylation of HMGB1. The succinylation of HMGB1 at the K90 promoted the protein stability and induced the enrichment of HMGB1 in cytoplasm, which induced the calcification in VSMCs. Together, 12,13-diHOME attenuates high glucose-induced calcification in VSMCs through repressing CPT1A-mediated HMGB1 succinylation.


Sujet(s)
Carnitine O-palmitoyltransferase , Glucose , Protéine HMGB1 , Muscles lisses vasculaires , Myocytes du muscle lisse , Calcification vasculaire , Humains , Muscles lisses vasculaires/métabolisme , Muscles lisses vasculaires/anatomopathologie , Muscles lisses vasculaires/effets des médicaments et des substances chimiques , Carnitine O-palmitoyltransferase/métabolisme , Carnitine O-palmitoyltransferase/génétique , Protéine HMGB1/métabolisme , Glucose/métabolisme , Glucose/pharmacologie , Mâle , Sujet âgé , Calcification vasculaire/métabolisme , Calcification vasculaire/anatomopathologie , Femelle , Myocytes du muscle lisse/métabolisme , Myocytes du muscle lisse/effets des médicaments et des substances chimiques , Myocytes du muscle lisse/anatomopathologie , Diabète de type 2/métabolisme , Diabète de type 2/anatomopathologie , Cellules cultivées
17.
Front Immunol ; 15: 1370516, 2024.
Article de Anglais | MEDLINE | ID: mdl-38605946

RÉSUMÉ

Background: Abdominal aortic calcification (AAC) pathogenesis is intricately linked with inflammation. The pan-immune-inflammation value (PIV) emerges as a potential biomarker, offering reflection into systemic inflammatory states and assisting in the prognosis of diverse diseases. This research aimed to explore the association between PIV and AAC. Methods: Employing data from the National Health and Nutrition Examination Survey (NHANES), this cross-sectional analysis harnessed weighted multivariable regression models to ascertain the relationship between PIV and AAC. Trend tests probed the evolving relationship among PIV quartiles and AAC. The study also incorporated subgroup analysis and interaction tests to determine associations within specific subpopulations. Additionally, the least absolute shrinkage and selection operator (LASSO) regression and multivariable logistic regression were used for characteristics selection to construct prediction model. Nomograms were used for visualization. The receiver operator characteristic (ROC) curve, calibration plot and decision curve analysis were applied for evaluate the predictive performance. Results: From the cohort of 3,047 participants, a distinct positive correlation was observed between PIV and AAC. Subsequent to full adjustments, a 100-unit increment in PIV linked to an elevation of 0.055 points in the AAC score (ß=0.055, 95% CI: 0.014-0.095). Categorizing PIV into quartiles revealed an ascending trend: as PIV quartiles increased, AAC scores surged (ß values in Quartile 2, Quartile 3, and Quartile 4: 0.122, 0.437, and 0.658 respectively; P for trend <0.001). Concurrently, a marked rise in SAAC prevalence was noted (OR values for Quartile 2, Quartile 3, and Quartile 4: 1.635, 1.842, and 2.572 respectively; P for trend <0.01). Individuals aged 60 or above and those with a history of diabetes exhibited a heightened association. After characteristic selection, models for predicting AAC and SAAC were constructed respectively. The AUC of AAC model was 0.74 (95%CI=0.71-0.77) and the AUC of SAAC model was 0.84 (95%CI=0.80-0.87). According to the results of calibration plots and DCA, two models showed high accuracy and clinical benefit. Conclusion: The research findings illuminate the potential correlation between elevated PIV and AAC presence. Our models indicate the potential utility of PIV combined with other simple predictors in the assessment and management of individuals with AAC.


Sujet(s)
Calcification vasculaire , Humains , Études transversales , Enquêtes nutritionnelles , Facteurs de risque , Calcification vasculaire/épidémiologie , Calcification vasculaire/anatomopathologie , Inflammation/complications
18.
Cell Signal ; 119: 111189, 2024 Jul.
Article de Anglais | MEDLINE | ID: mdl-38670475

RÉSUMÉ

In patients on maintenance hemodialysis (MHD), vascular calcification (VC) is an independent predictor of cardiovascular disease (CVD), which is the primary cause of death in chronic kidney disease (CKD). The main component of VC in CKD is the vascular smooth muscle cells (VSMCs). VC is an ordered, dynamic activity. Under the stresses of oxidative stress and calcium-­phosphorus imbalance, VSMCs undergo osteogenic phenotypic transdifferentiation, which promotes the formation of VC. In addition to traditional epigenetics like RNA and DNA control, post-translational modifications have been discovered to be involved in the regulation of VC in recent years. It has been reported that the process of osteoblast differentiation is impacted by catalytic histone or non-histone arginine methylation. Its function in the osteogenic process is comparable to that of VC. Thus, we propose that arginine methylation regulates VC via many signaling pathways, including as NF-B, WNT, AKT/PI3K, TGF-/BMP/SMAD, and IL-6/STAT3. It might also regulate the VC-related calcification regulatory factors, oxidative stress, and endoplasmic reticulum stress. Consequently, we propose that arginine methylation regulates the calcification of the arteries and outline the regulatory mechanisms involved.


Sujet(s)
Arginine , Calcification vasculaire , Animaux , Humains , Arginine/métabolisme , Méthylation , Muscles lisses vasculaires/métabolisme , Muscles lisses vasculaires/anatomopathologie , Stress oxydatif , Transduction du signal , Calcification vasculaire/métabolisme , Calcification vasculaire/anatomopathologie
19.
J Vasc Res ; 61(3): 122-128, 2024.
Article de Anglais | MEDLINE | ID: mdl-38547846

RÉSUMÉ

INTRODUCTION: We aimed to compare conventional vessel wall MR imaging techniques and quantitative susceptibility mapping (QSM) to determine the optimal sequence for detecting carotid artery calcification. METHODS: Twenty-two patients who underwent carotid vessel wall MR imaging and neck CT were enrolled. Four slices of 6-mm sections from the bilateral internal carotid bifurcation were subdivided into 4 segments according to clock position (0-3, 3-6, 6-9, and 9-12) and assessed for calcification. Two blinded radiologists independently reviewed a total of 704 segments and scored the likelihood of calcification using a 5-point scale on spin-echo imaging, FLASH, and QSM. The observer performance for detecting calcification was evaluated by a multireader, multiple-case receiver operating characteristic study. Weighted κ statistics were calculated to assess interobserver agreement. RESULTS: QSM had a mean area under the receiver operating characteristic curve of 0.85, which was significantly higher than that of any other sequence (p < 0.01) and showed substantial interreader agreement (κ = 0.68). A segment with a score of 3-5 was defined as positive, and a segment with a score of 1-2 was defined as negative; the sensitivity and specificity of QSM were 0.75 and 0.87, respectively. CONCLUSION: QSM was the most reliable MR sequence for the detection of plaque calcification.


Sujet(s)
Artériopathies carotidiennes , Biais de l'observateur , Plaque d'athérosclérose , Valeur prédictive des tests , Calcification vasculaire , Humains , Calcification vasculaire/imagerie diagnostique , Calcification vasculaire/anatomopathologie , Femelle , Mâle , Sujet âgé , Adulte d'âge moyen , Artériopathies carotidiennes/imagerie diagnostique , Artériopathies carotidiennes/anatomopathologie , Reproductibilité des résultats , Angiographie par résonance magnétique , Études rétrospectives , Sujet âgé de 80 ans ou plus , Angiographie par tomodensitométrie , Artère carotide interne/imagerie diagnostique , Artère carotide interne/anatomopathologie , Imagerie par résonance magnétique
20.
BMJ Open Diabetes Res Care ; 12(1)2024 Feb 08.
Article de Anglais | MEDLINE | ID: mdl-38336383

RÉSUMÉ

INTRODUCTION: There is conflicting evidence whether lower extremity arterial calcification coincides with coronary arterial calcification (CAC). The aims of this study were to investigate the associations between (1) femoral and crural calcification with CAC, and (2) femoral and crural calcification pattern with CAC. RESEARCH DESIGN AND METHODS: This cross-sectional study included 405 individuals (74% men, 62.6±10.9 years) from the ARTEMIS cohort study at high risk of cardiovascular disease (CVD) who underwent a CT scan of the femoral, crural and coronary arteries. High CVD risk was defined as history/presence of cerebrovascular disease, coronary artery disease, abdominal aortic aneurysm, renal artery stenosis, peripheral artery disease or CVD risk factors: diabetes mellitus type 2, hypertension, hyperlipidemia. Calcification score within each arterial bed was expressed in Agatston units. Dominant calcification patterns (intimal, medial, absent/indistinguishable) were determined via a CT-guided histologically validated scoring algorithm. Multivariable-adjusted multinomial logistic regression analyses were used. Replication was performed in an independent population of individuals with diabetes mellitus type 2 (Early-HFpEF cohort study). RESULTS: Every 100-point increase in femoral and crural calcification score was associated with 1.23 (95% CI=1.09 to 1.37, p<0.001) and 1.28 (95% CI=1.11 to 1.47, p=0.001) times higher odds of having CAC within tertile 3 (high) versus tertile 1 (low), respectively. The association appeared stronger for crural versus femoral arteries. Moreover, the presence of femoral intimal (OR=10.81, 95% CI=4.23 to 27.62, p<0.001), femoral medial (OR=10.37, 95% CI=3.92 to 27.38, p<0.001) and crural intimal (OR=6.70, 95% CI=2.73 to 16.43, p<0.001) calcification patterns were associated with higher odds of having CAC within tertile 3 versus tertile 1, independently from concomitant calcification score. This association appeared stronger for intimal versus medial calcification patterns. The replication analysis yielded similar results. CONCLUSIONS: Higher femoral and crural calcification scores were associated with higher CAC. Moreover, the presence of femoral intimal, femoral medial and crural intimal calcification patterns was associated with increased CAC. It appears that arterial calcification is a systemic process which occurs simultaneously in various arterial beds.


Sujet(s)
Maladies cardiovasculaires , Diabète de type 2 , Défaillance cardiaque , Calcification vasculaire , Mâle , Humains , Femelle , Vaisseaux coronaires/anatomopathologie , Études de cohortes , Calcification vasculaire/imagerie diagnostique , Calcification vasculaire/épidémiologie , Calcification vasculaire/anatomopathologie , Études transversales , Facteurs de risque , Débit systolique , Diabète de type 2/complications , Membre inférieur
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