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Lipocalin-2 Attenuates Vascular Calcification by Stabilizing Acadvl to Enhance Fatty Acid Oxidation

ABSTRACT: Vascular calcification (VC) is a critical contributor to cardiovascular mortality, driven by osteogenic differentiation of vascular smooth muscle cells (VSMCs) under hyperphosphatemia, yet molecular mechanisms remain incompletely defined. This study investigates the role of lipocalin-2 (LCN2) in regulating VC through both clinical and experimental approaches. We found LCN2 expression was significantly downregulated in calcified radial arteries from chronic kidney disease (CKD) patients and in VSMCs under calcifying conditions. Functionally, recombinant LCN2 protein or LCN2 overexpression attenuated calcification in VSMCs, arterial rings, and a CKD-associated VC mouse model, while LCN2 knockdown exacerbated these effects. Multi-omics analysis revealed that LCN2 enhanced fatty acid β-oxidation (FAO), and pharmacological inhibition of FAO accelerated calcification. Mechanistic studies using co-immunoprecipitation mass spectrometry combined with computational modeling identified a direct and stable interaction between LCN2 and very long-chain acyl-CoA dehydrogenase (Acadvl), a key mitochondrial FAO enzyme. We demonstrated that LCN2 stabilized Acadvl and enhanced its expression, while Acadvl knockdown abolished LCN2's protective effects against VC. These findings establish the LCN2-Acadvl axis as a novel regulatory mechanism mitigating VC through enhancing FAO, revealing promising therapeutic targets for vascular calcification pathology.

ORGANISM(S): Rattus Norvegicus

SUBMITTER: Mi Liu

PROVIDER: PXD068638 | iProX | Fri Sep 19 00:00:00 BST 2025

REPOSITORIES: iProX

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LCN2 Attenuates Vascular Calcification by Stabilizing Acadvl to Enhance Fatty Acid Oxidation

Project description:Vascular calcification (VC) is a critical contributor to cardiovascular mortality, driven by osteogenic differentiation of vascular smooth muscle cells (VSMCs) under hyperphosphatemia, yet molecular mechanisms remain incompletely defined. This study investigates the role of lipocalin-2 (LCN2) in regulating VC through both clinical and experimental approaches. We found LCN2 expression was significantly downregulated in calcified radial arteries from chronic kidney disease (CKD) patients and in VSMCs under calcifying conditions. Functionally, recombinant LCN2 protein or LCN2 overexpression attenuated calcification in VSMCs, arterial rings, and a CKD-associated VC mouse model, while LCN2 knockdown exacerbated these effects. Multi-omics analysis revealed that LCN2 enhanced fatty acid β-oxidation (FAO), and pharmacological inhibition of FAO accelerated calcification. Mechanistic studies using co-immunoprecipitation mass spectrometry combined with computational modeling identified a direct and stable interaction be

2025-09-19 | PXD068637 |

Dysfunctional Mesenchymal Stem Cell-derived Extracellular Vesicles in Chronic Kidney Disease: A Role in Vascular Calcification

Project description:Background: Vascular calcification (VC) is a severe complication of chronic kidney disease (CKD) and increases cardiovascular morbidity and mortality. Extracellular vesicles (EVs) from bone mesenchymal stem cells (BMSCs) may influence vascular health through intercellular communication. This study investigated how CKD alters the anti-calcific function of BMSC-derived EVs, focusing on microRNA content, particularly miR-29a-3p. Methods: EVs were isolated from healthy and CKD-affected BMSCs and assessed for size, uptake by vascular smooth muscle cells (VSMCs), and miRNA content. High-phosphate-treated VSMCs and CKD rat models of vascular calcification were used to evaluate the effects of EVs on VC. Circulating miR-29a-3p was measured in hemodialysis patients and correlated with VC severity. Results: EVs from both groups showed comparable size and VSMC uptake. However, CKD-derived EVs had an altered miRNA profile, including markedly reduced miR-29a-3p, and showed diminished ability to inhibit phosphate-induced calcification. Restoration of miR-29a-3p suppressed calcification in vitro and in vivo. In hemodialysis patients, circulating miR-29a-3p was inversely associated with calcification severity. Conclusions: CKD impairs the anti-calcific function of BMSC-derived EVs partly through downregulation of EV-associated miR-29a-3p. Restoring miR-29a-3p may help mitigate VC in CKD, and circulating miR-29a-3p may serve as a clinical biomarker.

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mRNA expression profile in vascular smooth muscle cells (VSMCs) after inducing calcification

Project description:Vascular calcification (VC) is often associated with cardiovascular and metabolic diseases. However, the molecular mechanisms linking VC to these diseases have yet to be elucidated. Here we report that MDM2-induced polyubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Loss of HDAC1 activity via either chemical inhibitor or genetic ablation enhanced VC. HDAC1 protein, but not mRNA, was reduced in cell and animal calcification models and in human calcified coronary artery. In the calcification-provoking condition, proteasomal degradation of HDAC1 preceded VC. The calcification-provoking condition induced MDM2 E3 ligase, which then resulted in HDAC1 K74 polyubiquitination. Overexpression of MDM2 enhanced VC, whereas loss of MDM2 blunted it. Decoy peptides spanning HDAC1 K74 and RG 7112, an MDM2 inhibitor, prevented VC in vivo and in vitro. These results demonstrate a previously unknown ubiquitination pathway and suggest MDM2-mediated HDAC1 polyubiquitination as a new therapeutic target in VC. Calcification was induced in rat aorta vascular smooth muscle cells with inorganic phosphate (Pi). Total RNA were extracted from the cells 3 and 6 days later. mRNA profile of the sample was compared with normal control.

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Signature analyses for circulating extracellular vesicle in chronic kidney disease

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Proteomic characterization of extracellular vesicles (EVs) released by primary human vascular smooth muscle cells (VSMCs) under calcification stress

Project description:Vascular calcification (VC) is a strong predictor of cardiovascular risk, particularly in chronic kidney disease (CKD) patients, associated with increased vascular stiffness, pulse pressure, left ventricular hypertrophy and atherosclerotic plaque burden [1]. VC is currently accepted as a highly controlled multifactorial process, where the release of extracellular vesicles (EVs) with calcification capacity plays an essential role in mediating cell-induced matrix mineralization [2]. Still, questions considering mechanisms of EVs deposition in the extracellular space, and its relationship with vesicle origin, loading, calcifying capacity and role in intercellular communication remain elusive. In this work we established a proteomic approach to characterize extracellular matrix (ECM)-deposited and cell media (CM) released EVs, from an in vitro model of VC consisting of primary vascular smooth muscle cells (VSMCs), bringing new knowledge into their specific characteristics and cargo.

2025-05-06 | PXD044045 | Pride

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Project description:Chronic kidney disease (CKD) is associated with increased cardiovascular risk, morphologically characterized by vascular calcification (VC). In CKD, high serum phosphate levels result in enhanced calcification propensity and the formation of circulating crystalline nanoaggregates (calciprotein particles, CPP2) containing calcium, phosphate and serum proteins. CPP2 can induce VC directly and this is recapitulated in vascular smooth muscle cells (VSMCs) in vitro. Under physiological conditions, vascular endothelial cells (ECs), rather than VSMCs are primarily exposed to circulating CPP2. Knowledge on the modulating effects of ECs on VC development is still in its infancy. The aim of this study was to investigate the paracrine signaling between ECs and VSMCs in CPP2-induced VC. To identify secreted soluble factors for CPP2-activated ECsthis factor, CPP2-activated ECs secretome was analyzed using mass spectrometry (LC/MS).

2023-11-30 | PXD047477 |

CKD-PROTEOME project, namely Calciprotein particle-activated endothelial cells exhibit altered mitochondria related to calcium dysregulation

Project description:Chronic kidney disease (CKD) is associated with increased cardiovascular risk, morphologically characterized by vascular calcification (VC). In CKD, high serum phosphate levels result in enhanced calcification propensity and the formation of circulating crystalline nanoaggregates (calciprotein particles, CPP2) containing calcium, phosphate and serum proteins. CPP2 can induce VC directly and this is recapitulated in vascular smooth muscle cells (VSMCs) in vitro. Under physiological conditions, vascular endothelial cells (ECs), rather than VSMCs are primarily exposed to circulating CPP2. Knowledge on the modulating effects of ECs on VC development is still in its infancy. The aim of this study was to investigate the calcium and bioenergetics signaling in CPP2-induced EC, including using ECs global proteome.

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