Platelet Membrane-Coated Alterbrassicene a Nanoparticle Inhibits Calcification of the Aortic Valve by Suppressing Phosphorylation P65 NF-κB

Abstract

Calcific aortic valve disease (CAVD) is a leading cause of cardiovascular mortality and morbidity with increasing prevalence and incidence. However, there is currently no effective drug treatment for CAVD. In this study, we established Immortal human valve interstitial cells (VICs) to perform a drug screening for our in-house natural product library. The natural fusicoccane diterpenoid alterbrassicene A (ABA) was found to significantly reduce the calcification of human VICs during osteogenic induction through inhibiting the phosphorylation P65. Runt-related transcription factor 2 and bone morphogenetic protein-2 were down regulated with the treatment of ABA in human VICs. Additonally, molecular docking results revealed that ABA bound to RelA (P65) protein. Phosphorylation of P65 (Ser536) was alleviated by ABA treatment, as well as the nuclear translocation of P65 during osteogenic induction in human VICs. Alizarin Red staining showed that ABA inhibited osteogenic differentiation of VICs in a dose-dependent manner. Platelet membrane-coated ABA nanoparticles were used in a wire-induced aortic valve stenosis model to conduct precise therapy of the aortic valve. In summary, our current research highlights a novel natural compound, ABA, as a promising candidate to prevent the progression of calcified aortic valve disease.

Note:
Funding Information: This work was supported by the National Key R&D Program of China (Nos. 2021YFA1101900 and 2021YFA0910500), the National Natural Science Foundation of China (Nos. 81930052, 81873503, 82100303, and 82273811), the China Postdoctoral Science Foundation (No. 2021M701330), and the National Program for Support of Top notch Young Professionals (No. 0106514050).

Declaration of Interests: The authors declare no conflict of interest.

Ethics Approval Statement: All experiments involving humans were carried out per the Declaration of Helsinki and approved by the Review Board of Tongji Medical College, Huazhong University of Science and Technology (#IORG0003571). Written informed consent was obtained from all the participants.

All animal experiments were approved by the Animal Care and Use Committee of Tongji Medical College (IACUC#2843).

Keywords: natural product, calcific aortic valve disease, immortalization, NF-κB, nanoparticle