Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.
Department of Physics, Center for Disease Proteomics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan.
Sci Rep. 2021 Jul 14;11(1):14470. doi: 10.1038/s41598-021-93862-w.
We recently established a new plasma peptidomic technique and comprehensively identified a large number of low-molecular weight and low-abundance native peptides using a single drop of human plasma. To discover a novel polypeptide that potently modulates the cardiovascular system, we performed a bioinformatics analysis of the large-scale identification results, sequentially synthesized the selected peptide sequences, tested their biological activities, and identified a 30-amino-acid proatherogenic peptide, GIP_HUMAN[22-51], as a potent proatherosclerotic peptide hormone. GIP_HUMAN[22-51] has a common precursor with the glucose-dependent insulinotropic polypeptide (GIP) and is located immediately N-terminal to GIP. Chronic infusion of GIP_HUMAN[22-51] into ApoE mice accelerated the development of aortic atherosclerotic lesions, which were inhibited by co-infusions with an anti-GIP_HUMAN[22-51] antibody. GIP_HUMAN[22-51] increased the serum concentrations of many inflammatory and proatherogenic proteins, whereas neutralising antibodies reduced their levels. GIP_HUMAN[22-51] induced IκB-α degradation and nuclear translocation of NF-κB in human vascular endothelial cells and macrophages. Immunoreactive GIP_HUMAN[22-51] was detected in human tissues but there was no colocalization with the GIP. The plasma GIP_HUMAN[22-51] concentration in healthy humans determined using a stable-isotope tagged peptide was approximately 0.6 nM. This study discovered a novel endogenous proatherogenic peptide by using a human plasma native peptidomic resource.
我们最近建立了一种新的血浆肽组学技术，通过使用人类血浆中的单滴，全面鉴定了大量低分子量和低丰度的天然肽。为了发现一种能有效调节心血管系统的新型多肽，我们对大规模鉴定结果进行了生物信息学分析，依次合成了选定的肽序列，测试了它们的生物学活性，并鉴定出一种 30 个氨基酸的前动脉粥样硬化肽，GIP_HUMAN[22-51]，作为一种有效的动脉粥样硬化肽激素。GIP_HUMAN[22-51]与葡萄糖依赖性胰岛素样多肽 (GIP) 具有共同的前体，并且位于 GIP 的 N 端。GIP_HUMAN[22-51] 持续输注到 ApoE 小鼠中加速了主动脉粥样硬化病变的发展，而用抗 GIP_HUMAN[22-51] 抗体共输注则抑制了病变的发展。GIP_HUMAN[22-51] 增加了许多炎症和前动脉粥样硬化蛋白的血清浓度，而中和抗体则降低了它们的水平。GIP_HUMAN[22-51] 在人血管内皮细胞和巨噬细胞中诱导 IκB-α 降解和 NF-κB 的核转位。在人组织中检测到免疫反应性的 GIP_HUMAN[22-51]，但与 GIP 没有共定位。使用稳定同位素标记肽测定的健康人类血浆中 GIP_HUMAN[22-51] 的浓度约为 0.6 nM。本研究通过使用人类血浆天然肽组学资源发现了一种新型的内源性前动脉粥样硬化肽。
