The matrix metalloproteinases 2 and 9 initiate uraemic vascular calcifications

Hecht, Eva; Freise, Christian; Websky, Karoline von; Nasser, Hamoud; Kretzschmar, Nadja; Stawowy, Philipp; Hocher, Berthold; Querfeld, Uwe

doi:10.1093/ndt/gfv321

Cited by 54 publications

(33 citation statements)

References 32 publications

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“…Like calcification, cartilaginous metaplasia is poorly defined. However, a balance in proangiogenic factors, fibroblast populations, and extracellular matrix enzymes has been postulated to play a role in regulating ossification in the vessel wall (40)(41)(42). Consistent with these disruptive changes in the BCA, we found a corresponding increase in Mac-3 positive areas in the Apoe −/− /Treml4 −/− mice (Figure 6D), which suggest that Treml4 deficiency delays the fibrotic mechanisms in the BCA.…”

Section: Treml4 Regulates Extracellular Matrix Depositionsupporting

confidence: 72%

TREML4 Promotes Inflammatory Programs in Human and Murine Macrophages and Alters Atherosclerosis Lesion Composition in the Apolipoprotein E Deficient Mouse

et al. 2020

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Frontiers in Immunology | www.frontiersin.org March 2020 | Volume 11 | Article 397Gonzalez-Cotto et al. Treml4 in Macrophages and AtherosclerosisMetabolomic analysis confirmed that Treml4 deficiency may promote a beneficial relationship between iron homeostasis and glucose metabolism. Together, our results suggest that Treml4 plays a role in the development of cardiovascular disease, as indicated by Treml4-dependent dysregulation of macrophage inflammatory pathways, macrophage metabolism and promotion of vulnerability features in advanced lesions.

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Section: Treml4 Regulates Extracellular Matrix Depositionsupporting

confidence: 72%

TREML4 Promotes Inflammatory Programs in Human and Murine Macrophages and Alters Atherosclerosis Lesion Composition in the Apolipoprotein E Deficient Mouse

et al. 2020

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“…Similarly, Fibulin-3 reduces phosphate-induced MMP2 and MMP9 expression in VSMCs. Gelatinases are essential for phenotypical transformation of VSMCs, matrix remodeling and initiation of vascular calcification [57, 58] by up-regulation of bone morphogenetic protein-2 (BMP-2) which induces the expression of CBFA1 and MSX2 [59]. Furthermore, oxidative stress is able to induce apoptosis of VSMCs [60] and apoptosis may promote the initiation and progression of vascular calcification [61].…”

Section: Discussionmentioning

confidence: 99%

Fibulin-3 Attenuates Phosphate-Induced Vascular Smooth Muscle Cell Calcification by Inhibition of Oxidative Stress

Luong

Schelski

Boehme

et al. 2018

Cell Physiol Biochem

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Background/Aims: Fibulin-3, an extracellular matrix glycoprotein, inhibits vascular oxidative stress and remodeling in hypertension. Oxidative stress is prevalent in chronic kidney disease (CKD) patients and is an important mediator of osteo-/chondrogenic transdifferentiation and calcification of vascular smooth muscle cells (VSMCs) during hyperphosphatemia. Therefore, the present study explored the effects of Fibulin-3 on phosphate-induced vascular calcification. Methods: Experiments were performed in primary human aortic smooth muscle cells (HAoSMCs) treated with control or with phosphate without or with additional treatment with recombinant human Fibulin-3 protein or with hydrogen peroxide as an exogenous source of oxidative stress. Results: Treatment with calcification medium significantly increased calcium deposition in HAoSMCs, an effect significantly blunted by additional treatment with Fibulin-3. Moreover, phosphate-induced alkaline phosphatase activity and mRNA expression of osteogenic and chondrogenic markers MSX2, CBFA1, SOX9 and ALPL were all significantly reduced by addition of Fibulin-3. These effects were paralleled by similar regulation of oxidative stress in HAoSMCs. Phosphate treatment significantly up-regulated mRNA expression of the oxidative stress markers NOX4 and CYBA, down-regulated total antioxidant capacity and increased the expression of downstream effectors of oxidative stress PAI-1, MMP2 and MMP9 as well as BAX/BLC2 ratio in HAoSMCs, all effects blocked by additional treatment with Fibulin-3. Furthermore, the protective effects of Fibulin-3 on phosphate-induced osteogenic and chondrogenic markers expression in HAoSMCs were reversed by additional treatment with hydrogen peroxide. Conclusions: Fibulin-3 attenuates phosphate-induced osteo-/ chondrogenic transdifferentiation and calcification of VSMCs, effects involving inhibition of oxidative stress. Up-regulation or supplementation of Fibulin-3 may be beneficial in reducing the progression of vascular calcification during hyperphosphatemic conditions such as CKD.

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“…It might be also involved in the development of medial layer vascular calcification in uremic rats (Kumata et al, ). Both gelatinases provide essential signals for phenotypic VSMC conversion, matrix remodeling and the initiation of vascular calcification (Hecht et al, , p. 9). MMP‐2 and 9 were also shown to promote vascular calcification by upregulating bone morphogenetic protein 2 (BMP‐2) which induces expression of RUNX2 and msh‐homeobox 2 (Msx‐2), two proteins associated with phenotype transition of VSMCs in vascular calcification (Zhao et al, ).…”

Section: Discussionmentioning

confidence: 99%

Characterization and assessment of potential microRNAs involved in phosphate‐induced aortic calcification

Fakhry

Skafi

Fayyad‐Kazan

et al. 2017

Journal Cellular Physiology

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Medial artery calcification, a hallmark of type 2 diabetes mellitus and chronic kidney disease (CKD), is known as an independent risk factor for cardiovascular mortality and morbidity. Hyperphosphatemia associated with CKD is a strong stimulator of vascular calcification but the molecular mechanisms regulating this process remain not fully understood. We showed that calcification was induced after exposing Sprague-Dawley rat aortic explants to high inorganic phosphate level (P , 6 mM) as examined by Alizarin red and Von Kossa staining. This calcification was associated with high Tissue-Nonspecific Alkaline Phosphatase (TNAP) activity, vascular smooth muscle cells de-differentiation, manifested by downregulation of smooth muscle 22 alpha (SM22α) protein expression which was assessed by immunoblot analysis, immunofluorescence, and trans-differentiation into osteo-chondrocyte-like cells revealed by upregulation of Runt related transcription factor 2 (Runx2), TNAP, osteocalcin, and osteopontin mRNA levels which were determined by quantitative real-time PCR. To unravel the possible mechanism(s) involved in this process, microRNA (miR) expression profile, which was assessed using TLDA technique and thereafter confirmed by individual qRT-PCR, revealed differential expression 10 miRs, five at day 3 and 5 at day 6 post P treatment versus control untreated aortas. At day 3, miR-200c, -155, 322 were upregulated and miR-708 and 331 were downregulated. After 6 days of treatment, miR-328, -546, -301a were upregulated while miR-409 and miR-542 were downregulated. Our results indicate that high P levels trigger aortic calcification and modulation of certain miRs. These observations suggest that mechanisms regulating aortic calcification might involve miRs, which warrant further investigations in future studies.

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The matrix metalloproteinases 2 and 9 initiate uraemic vascular calcifications

Abstract: These data indicate that both gelatinases provide essential signals for phenotypic VSMC conversion, matrix remodelling and the initiation of vascular calcification. Their inhibition seems a promising strategy in the prevention of vascular calcifications.

Cited by 54 publications

References 32 publications

TREML4 Promotes Inflammatory Programs in Human and Murine Macrophages and Alters Atherosclerosis Lesion Composition in the Apolipoprotein E Deficient Mouse

TREML4 Promotes Inflammatory Programs in Human and Murine Macrophages and Alters Atherosclerosis Lesion Composition in the Apolipoprotein E Deficient Mouse

Fibulin-3 Attenuates Phosphate-Induced Vascular Smooth Muscle Cell Calcification by Inhibition of Oxidative Stress

Characterization and assessment of potential microRNAs involved in phosphate‐induced aortic calcification

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