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Empagliflozin alleviates atherosclerotic calcification by inhibiting osteogenic differentiation of vascular smooth muscle cells

ABSTRACT: SGLT-2 inhibitors, such as empagliflozin, have been shown to reduce the occurrence of cardiovascular events and delay the progression of atherosclerosis. However, its role in atherosclerotic calcification remains unclear. In this research, ApoE-/- mice were fed with western diet and empagliflozin was added to the drinking water for 24 weeks. Empagliflozin treatment significantly alleviated arterial calcification assessed by alizarin red and von kossa staining in aortic roots and reduced the lipid levels, while had little effect on body weight and blood glucose levels in ApoE-/- mice. In vitro studies, empagliflozin significantly inhibits calcification of primary vascular smooth muscle cells (VSMCs) and aortic rings induced by osteogenic media (OM) or inorganic phosphorus (Pi). RNA sequencing of VSMCs cultured in OM with or without empagliflozin showed that empagliflozin negatively regulated the osteogenic differentiation of VSMCs. And further studies confirmed that empagliflozin significantly inhibited osteogenic differentiation of VSMCs via qRT-PCR. Our study demonstrates that empagliflozin alleviates atherosclerotic calcification by inhibiting osteogenic differentiation of VSMCs, which addressed a critical need for the discovery of a drug-based therapeutic approach in the treatment of atherosclerotic calcification.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE243752 | GEO | 2023/11/22

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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Empagliflozin alleviates atherosclerotic calcification by inhibiting osteogenic differentiation of vascular smooth muscle cells

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