Department of Medical Biophysics, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada; Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
Department of Medical Biophysics, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
J Biol Chem. 2023 Mar;299(3):102921. doi: 10.1016/j.jbc.2023.102921. Epub 2023 Jan 19.
Circulating fatty acid-binding protein 3 (FABP3) is an effective biomarker of myocardial injury and peripheral artery disease (PAD). The endothelium, which forms the inner most layer of every blood vessel, is exposed to higher levels of FABP3 in PAD or following myocardial injury, but the pathophysiological role of endothelial FABP3, the effect of FABP3 exposure on endothelial cells, and related mechanisms are unknown. Here, we aimed to evaluate the pathophysiological role of endothelial FABP3 and related mechanisms in vitro. Our molecular and functional in vitro analyses show that (1) FABP3 is basally expressed in endothelial cells; (2) inflammatory stress in the form of lipopolysaccharide (LPS) upregulated endothelial FABP3 expression; (3) loss of endogenous FABP3 protected endothelial cells against LPS-induced endothelial dysfunction; however, exogenous FABP3 exposure exacerbated LPS-induced inflammation; (4) loss of endogenous FABP3 protected against LPS-induced endothelial dysfunction by promoting cell survival and anti-inflammatory and pro-angiogenic signaling pathways. Together, these findings suggest that gain-of endothelial FABP3 exacerbates, whereas loss-of endothelial FABP3 inhibits LPS-induced endothelial dysfunction by promoting cell survival and anti-inflammatory and pro-angiogenic signaling. We propose that an increased circulating FABP3 in myocardial injury or PAD patients may be detrimental to endothelial function, and therefore, therapies aimed at inhibiting FABP3 may improve endothelial function in diseased states.
循环脂肪酸结合蛋白 3（FABP3）是心肌损伤和外周动脉疾病（PAD）的有效生物标志物。内皮细胞形成了每根血管的最内层，在 PAD 或心肌损伤后，内皮细胞暴露于更高水平的 FABP3 中，但内皮细胞 FABP3 的病理生理作用、FABP3 暴露对内皮细胞的影响以及相关机制尚不清楚。在这里，我们旨在评估内皮细胞 FABP3 的病理生理作用及其相关机制。我们的分子和功能体外分析表明：（1）FABP3 在血管内皮细胞中基础表达；（2）以脂多糖（LPS）形式的炎症应激上调内皮细胞 FABP3 表达；（3）内源性 FABP3 的缺失可保护内皮细胞免受 LPS 诱导的内皮功能障碍；然而，外源性 FABP3 的暴露加剧了 LPS 诱导的炎症；（4）内源性 FABP3 的缺失通过促进细胞存活和抗炎及促血管生成信号通路来保护内皮细胞免受 LPS 诱导的内皮功能障碍。总之，这些发现表明，内皮 FABP3 的增加会加剧，而内皮 FABP3 的缺失则通过促进细胞存活和抗炎及促血管生成信号通路来抑制 LPS 诱导的内皮功能障碍。我们提出，心肌损伤或 PAD 患者中循环 FABP3 的增加可能对内皮功能有害，因此，旨在抑制 FABP3 的治疗可能会改善疾病状态下的内皮功能。
