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Dendrophenol inhibits vascular calcification by activating IL13RA2-dependent inhibition of STAT3 and attenuating WNT3/b-catenin signaling pathway

ABSTRACT: In this experiment,we used HASMCs cells to explore the mechanisms by which Dendrophenol affects smooth muscle cell osteogenic differentiation and related mechanisms. We found that IL13RA2 expression was significantly reduced during the induction of osteogenic differentiation in HASMCs, and normal levels were restored after Dendrophenol treatment, thus Dendrophenol may treat vascular calcification through IL13RA2. Further, we found that IL13RA2 interacts with the transcription factor STAT3, suggesting that the therapeutic effect of Dendrophenol may be mediated through STAT3. In addition, we further investigated the link between IL13RA2/STAT3 and the classical WNT/b-catenin pathway and found that WNT3 plays an important role in this process. The mechanism of action of Dendrophenol was further clarified.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234356 | GEO | 2025/02/05

REPOSITORIES: GEO

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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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Dendrophenol inhibits vascular calcification by activating IL13RA2-dependent inhibition of STAT3 and attenuating WNT3/b-catenin signaling pathway

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