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BGP-15 抑制高磷诱导的高血糖加重的血管平滑肌细胞钙化。

BGP-15 Inhibits Hyperglycemia-Aggravated VSMC Calcification Induced by High Phosphate.

机构信息

Division of Nephrology, Department of Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.

Kálmán Laki Doctoral School, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.

出版信息

Int J Mol Sci. 2021 Aug 26;22(17):9263. doi: 10.3390/ijms22179263.

DOI:10.3390/ijms22179263
PMID:34502172
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8431374/
Abstract

Vascular calcification associated with high plasma phosphate (Pi) level is a frequent complication of hyperglycemia, diabetes mellitus, and chronic kidney disease. BGP-15 is an emerging anti-diabetic drug candidate. This study was aimed to explore whether BGP-15 inhibits high Pi-induced calcification of human vascular smooth muscle cells (VSMCs) under normal glucose (NG) and high glucose (HG) conditions. Exposure of VSMCs to Pi resulted in accumulation of extracellular calcium, elevated cellular Pi uptake and intracellular pyruvate dehydrogenase kinase-4 (PDK-4) level, loss of smooth muscle cell markers (ACTA, TAGLN), and enhanced osteochondrogenic gene expression (KLF-5, Msx-2, Sp7, BMP-2). Increased Annexin A2 and decreased matrix Gla protein (MGP) content were found in extracellular vesicles (EVs). The HG condition markedly aggravated Pi-induced VSMC calcification. BGP-15 inhibited Pi uptake and PDK-4 expression that was accompanied by the decreased nuclear translocation of KLF-5, Msx-2, Sp7, retained VSMC markers (ACTA, TAGLN), and decreased BMP-2 in both NG and HG conditions. EVs exhibited increased MGP content and decreased Annexin A2. Importantly, BGP-15 prevented the deposition of calcium in the extracellular matrix. In conclusion, BGP-15 inhibits Pi-induced osteochondrogenic phenotypic switch and mineralization of VSMCs in vitro that make BGP-15 an ideal candidate to attenuate both diabetic and non-diabetic vascular calcification.

摘要

高血浆磷酸盐（Pi）水平与血管钙化有关，是高血糖、糖尿病和慢性肾脏病的常见并发症。BGP-15 是一种新兴的抗糖尿病药物候选物。本研究旨在探讨 BGP-15 是否能抑制高 Pi 在正常葡萄糖（NG）和高葡萄糖（HG）条件下诱导的人血管平滑肌细胞（VSMCs）钙化。VSMCs 暴露于 Pi 会导致细胞外钙积累、细胞内 Pi 摄取增加和丙酮酸脱氢酶激酶-4（PDK-4）水平升高、平滑肌细胞标志物（ACTA、TAGLN）丢失，并增强成骨软骨基因表达（KLF-5、Msx-2、Sp7、BMP-2）。细胞外囊泡（EVs）中发现 Annexin A2 增加和基质 Gla 蛋白（MGP）含量减少。HG 条件明显加重 Pi 诱导的 VSMC 钙化。BGP-15 抑制 Pi 摄取和 PDK-4 表达，同时伴有 KLF-5、Msx-2、Sp7 的核转位减少、VSMC 标志物（ACTA、TAGLN）保留和 BMP-2 在 NG 和 HG 条件下减少。EVs 中 MGP 含量增加，Annexin A2 减少。重要的是，BGP-15 可防止细胞外基质中钙的沉积。总之，BGP-15 抑制 Pi 诱导的 VSMCs 体外成骨软骨表型转换和矿化，使 BGP-15 成为减轻糖尿病和非糖尿病血管钙化的理想候选药物。

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