A Proteomic Screen to Unravel the Molecular Pathways Associated with Warfarin-Induced or TNAP-Inhibited Arterial Calcification in Rats.
Britt OpdebeeckEllen NevenStuart MaudsleyHanne LeysenDeborah WalterHilde GerylPatrick C D'HaeseAnja VerhulstPublished in: International journal of molecular sciences (2023)
Arterial media calcification refers to the pathological deposition of calcium phosphate crystals in the arterial wall. This pathology is a common and life-threatening complication in chronic kidney disease, diabetes and osteoporosis patients. Recently, we reported that the use of a TNAP inhibitor, SBI-425, attenuated arterial media calcification in a warfarin rat model. Employing a high-dimensionality unbiased proteomic approach, we also investigated the molecular signaling events associated with blocking arterial calcification through SBI-425 dosing. The remedial actions of SBI-425 were strongly associated with (i) a significant downregulation of inflammatory (acute phase response signaling) and steroid/glucose nuclear receptor signaling (LXR/RXR signaling) pathways and (ii) an upregulation of mitochondrial metabolic pathways (TCA cycle II and Fatty Acid β-oxidation I). Interestingly, we previously demonstrated that uremic toxin-induced arterial calcification contributes to the activation of the acute phase response signaling pathway. Therefore, both studies suggest a strong link between acute phase response signaling and arterial calcification across different conditions. The identification of therapeutic targets in these molecular signaling pathways may pave the way to novel therapies against the development of arterial media calcification.
Keyphrases
- signaling pathway
- chronic kidney disease
- end stage renal disease
- pi k akt
- cell proliferation
- oxidative stress
- epithelial mesenchymal transition
- type diabetes
- escherichia coli
- atrial fibrillation
- newly diagnosed
- endothelial cells
- drug induced
- hydrogen peroxide
- blood pressure
- induced apoptosis
- metabolic syndrome
- skeletal muscle
- direct oral anticoagulants
- single molecule
- single cell
- poor prognosis
- patient reported outcomes
- body composition