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

ABSTRACT: 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.

ORGANISM(S): Homo Sapiens

SUBMITTER: Laurent Chatre

PROVIDER: PXD049245 | iProX | Tue Feb 06 00:00:00 GMT 2024

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

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