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LCN2 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 be

ORGANISM(S): Rattus Norvegicus

SUBMITTER: Mi Liu

PROVIDER: PXD068637 | iProX | Fri Sep 19 00:00:00 BST 2025

REPOSITORIES: iProX

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Project description:Vascular Calcification (VC) is a life threatening cardiovascular complication that accounts for high death rates particularly in association with diabetes, atherosclerosis and Chronic Kidney Disease (CKD. during VC, Vascular Smooth Muscle Cells (VSMCs) undergo reprogramming into osteoblast-like cells in response to calcium and phosphate mineral imbalance in CKD patients. This osteogenic switch is driven by the expression of several bone markers such as Runt- related transcription factor 2 (Runx2), Alkaline Phosphatase (ALP), Osteopontin (OPN), Matrix-Gla Protein (MGP), Osteocalcin (OCN), Type I Collagen (COL1), and Bone Sialo Proteins (BSPs). Recent studies showed that VSMCs secrete heterogeneous populations of Extracellular Vesicles (EVs)11 that are enriched under physiological conditions by calcification inhibitors such as Fetuin-A and MGP12,13,14. Interestingly, under pathological conditions, secreted EVs have a pro-calcifying profile and thereby act as nucleating foci for hydroxyapatite crystallization and propagation11,15. Electron Microscopy based studies revealed that EVs were embedded between collagen and elastin fibrils of arterial walls suggesting that calcification can be initiated through the EVs’ direct physical interaction with them13,16. We previously showed that a specific oligogalacturonic acid with a degree of polymerization of 8 (DP8) was able to inhibit vascular calcification. This inhibition was partly due to a decrease of osteogenic markers’s expression but also to the masking of a consensus sequence found in COL1 i.e. GFOGER sequence, thus preventing EVs from binding to COL1. Although the use of DP8 in-vivo seems to be compromised due to probable enzymatic digestion, these results suggested that the inhibition of VSMCs’ osteogenic switch and the prevention of EVs-COL1 interaction could represent new potential therapeutic targets for inhibiting VC17. Since we have already showed that the triple-helical GFOGER consensus sequence forms a preferential binding site for EVs17, we thereby chemically synthesized a GFOGER peptide in order to determine its ability to inhibit VC on VSMCs and on an aortic ring ex-vivo model. We also aim to decipher the mechanisms of inhibition by investigating the osteogenic markers’ expression as well as the protein content of secreted EVs in the presence of the GFOGER peptide.

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

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