The FKBPL-based therapeutic peptide, AD-01, protects the endothelium from hypoxia-induced damage by stabilising hypoxia inducible factor-α and inflammation

• DOI: 10.1186/s12967-025-06118-w
• Publication Date: 2025-03-11T11:25:56Z
• Authors: Sahar Ghorbanpour; Siân Peta Cartland; Hao Chen; Sanchit Seth; Rupert C. Ecker; Claire Richards; Dunja Aksentijevic; Matthew P. Padula; Louise Cole; Majid Ebrahimi Wa...; Mary Meltem Kavurma; Lana McClements
• Keywords: Hypoxia

Abstract Background Endothelial dysfunction is a hallmark feature of cardiovascular disease (CVD), yet the underlying mechanisms are still poorly understood. This has impeded development effective therapies, particularly for peripheral artery disease. FK506-binding protein like (FKBPL) and its therapeutic peptide mimetic, AD-01, crucial negative regulators angiogenesis, however their roles in CVD unknown. In this study, we aimed to elucidate FKBPL-mediated involved regulating endothelial induced by hypoxia or inflammation, determine whether AD-01 can effectively restore function under these conditions. Methods Hindlimb ischemia was mice ligating proximal distal ends right femoral artery, and, after three days, gastrocnemius muscle collected immunofluorescence staining, RNA extraction. A 3D vitro microfluidics model developed cell migration impact FKBPL following treatments with: (i) 24 µM targeted siRNA, (ii) 1 mM inducible factor (HIF-1)α activator (DMOG), (iii) 50% (v/v) macrophage conditioned media (MCM), ± 100 nM AD-01. Unbiased, untargeted proteomic analysis conducted via LC-MS/MS identify targets Results expression substantially downregulated hindlimb ( p < 0.05, protein; 0.001, mRNA), correlating with increased neovascularization altered vascular adhesion molecule expression. our real-time advanced model, suppressed 0.05) VE-cadherin 0.001) expression, leading number 0.001), which restored treatment 0.01). Under inflammatory conditions, 0.01) HIF-1α elevated, 0.05). Unlike hypoxia, did not influence but normalized CD31 P 0.05), microfluidic culture. Proteomic revealed that enhanced abundance tissue remodelling integrity proteins including collagen alpha-1(XIX) chain junctional cadherin associated-5 (JCAD) proteins. Conclusions represents an important novel mechanism inflammation-induced angiogenesis. The FKBPL-based peptide, could be viable option CVD-related dysfunction.