Maimonides Biomedical Research Institute of Córdoba (IMIBIC), University of Córdoba, Avda Menéndez Pidal s/n, 14004, Córdoba, Spain.
Cellular Biology, Physiology and Immunology Department, University of Córdoba, Córdoba, Spain.
J Transl Med. 2024 Nov 6;22(1):1003. doi: 10.1186/s12967-024-05748-w.
Vasculogenic therapies explored for the treatment of peripheral artery disease (PAD) have encountered minimal success in clinical trials. Addressing this, B55α, an isoform of protein phosphatase 2A (PP2A), emerges as pivotal in vessel remodeling through activation of hypoxia-inducible factor 1α (HIF-1α). This study delves into the pharmacological profile of VCE-004.8 (Etrinabdione) and evaluates its efficacy in a preclinical model of critical limb ischemia, with a focus on its potential as a PP2A/B55α activator to induce angiogenesis and arteriogenesis.
Vascular endothelial cells were used for in vitro experiments. Aorta ring assay was performed to explore sprouting activity. Matrigel plug-in assay was used to assess the angiogenic potential. Critical limb ischemia (CLI) in mice was induced by double ligation in the femoral arteria. Endothelial vascular and fibrotic biomarkers were studied by immunohistochemistry and qPCR. Arteriogenesis was investigated by microvascular casting and micro-CT. Proteomic analysis in vascular tissues was analyzed by LC-MS/MS. Ex-vivo expression of B55α and biomarkers were investigated in artery samples from PAD patients.
VCE-004.8 exhibited the ability to induce B55α expression and activate the intersecting pathways B55α/AMPK/Sirtuin 1/eNOS and B55α/PHD2/HIF-1α. VCE-004.8 prevented OxLDL and HO-induced cytotoxicity, senescence, and inflammation in endothelial cells. Oral VCE-004.8 increased aorta sprouting in vitro and angiogenesis in vivo. In CLI mice VCE-004.8 improved collateral vessel formation and induced endothelial cells proliferation, angiogenic gene expression and prevented fibrosis. The expression of B55α, Caveolin 1 and Sirtuin-1 is reduced in arteries from CLI mice and PAD patient, and the expression of these markers was restored in mice treated with VCE-004.8.
The findings presented in this study indicate that Etrinabdione holds promise in mitigating endothelial cell damage and senescence, while concurrently fostering arteriogenesis and angiogenesis. These observations position Etrinabdione as a compelling candidate for the treatment of PAD, and potentially other cardiovascular disorders.
在外周动脉疾病（PAD）的治疗中探索的血管生成疗法在临床试验中收效甚微。B55α 是蛋白磷酸酶 2A（PP2A）的一种同工型，通过激活缺氧诱导因子 1α（HIF-1α），在血管重塑中起着关键作用。本研究深入探讨了 VCE-004.8（埃替拉宾酮）的药理学特征，并评估了其在临界肢体缺血的临床前模型中的疗效，重点关注其作为 PP2A/B55α 激活剂诱导血管生成和动脉生成的潜力。
使用血管内皮细胞进行体外实验。进行主动脉环实验以探索发芽活性。使用 Matrigel 插件实验评估血管生成潜力。通过股动脉双重结扎诱导小鼠临界肢体缺血（CLI）。通过免疫组织化学和 qPCR 研究内皮血管和纤维化生物标志物。通过微血管铸造和微 CT 研究动脉生成。通过 LC-MS/MS 分析血管组织的蛋白质组学分析。通过从 PAD 患者的动脉样本中进行离体表达 B55α 和生物标志物的研究。
VCE-004.8 表现出诱导 B55α 表达和激活 B55α/AMPK/Sirtuin 1/eNOS 和 B55α/PHD2/HIF-1α 相交途径的能力。VCE-004.8 可防止 OxLDL 和 HO 诱导的内皮细胞细胞毒性、衰老和炎症。口服 VCE-004.8 增加了体外主动脉发芽和体内血管生成。在 CLI 小鼠中，VCE-004.8 改善了侧支血管形成，并诱导内皮细胞增殖、血管生成基因表达并预防纤维化。CLI 小鼠和 PAD 患者的动脉中 B55α、小窝蛋白 1 和 Sirtuin-1 的表达减少，而 VCE-004.8 治疗的小鼠中这些标志物的表达得到恢复。
本研究的结果表明，埃替拉宾酮有望减轻内皮细胞损伤和衰老，同时促进动脉生成和血管生成。这些观察结果使埃替拉宾酮成为治疗 PAD 甚至其他心血管疾病的有前途的候选药物。
