From the Centre of Marine Sciences (C.S.B.V., L.S., D.C.S.), GenoGla Diagnostics, Centre of Marine Sciences (C.S.B.V., D.C.S.), and Department of Biomedical Sciences and Medicine (A.P.S., P.L.N.), University of Algarve, Faro, Portugal; UCIBIO-REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Caparica, Portugal (A.L.M., R.M.); Centro de Investigação Interdisciplinar Egas Moniz, Egas Moniz-Cooperativa de Ensino Superior CRL, Caparica, Portugal (A.A.M.); Nephrology Department, Centro Hospitalar do Algarve, Faro, Portugal (A.P.S., P.L.N.); VIB-UGent Center for Medical Biotechnology Center and UGent Department of Biochemistry, Ghent, Belgium (A.S., K.G.); and R&D Group VitaK (C.V.) and Department of Biochemistry - Vascular Aspects, Faculty of Medicine, Health and Life Science (L.S.), Maastricht University, The Netherlands.
Arterioscler Thromb Vasc Biol. 2018 Mar;38(3):575-587. doi: 10.1161/ATVBAHA.117.310578. Epub 2018 Jan 4.
OBJECTIVE: Inhibition of mineral crystal formation is a crucial step in ectopic calcification. Serum calciprotein particles (CPPs) have been linked to chronic kidney disease (CKD) calcification propensity, but additional knowledge is required to understand their function, assemblage, and composition. The role of other circulating nanostructures, such as extracellular vesicles (EVs) in vascular calcification is currently unknown. Here, we investigated the association of GRP (Gla-rich protein) with circulating CPP and EVs and the role of CKD CPPs and EVs in vascular calcification. APPROACH AND RESULTS: Biological CPPs and EVs were isolated from healthy and CKD patients and comparatively characterized using ultrastructural, analytic, molecular, and immuno-based techniques. Our results show that GRP is a constitutive component of circulating CPPs and EVs. CKD stage 5 serum CPPs and EVs are characterized by lower levels of fetuin-A and GRP, and CPPs CKD stage 5 have increased mineral maturation, resembling secondary CPP particles. Vascular smooth muscle cell calcification assays reveal that CPPs CKD stage 5 and EVs CKD stage 5 are taken up by vascular smooth muscle cells and induce vascular calcification by promoting cell osteochondrogenic differentiation and inflammation. These effects were rescued by incubation of CPPs CKD stage 5 with γ-carboxylated GRP. In vitro, formation and maturation of basic calcium phosphate crystals was highly reduced in the presence of γ-carboxylated GRP, fetuin-A, and MGP (matrix gla protein), and a similar antimineralization system was identified in vivo. CONCLUSIONS: Uremic CPPs and EVs are important players in the mechanisms of widespread calcification in CKD. We propose a major role for cGRP as inhibitory factor to prevent calcification at systemic and tissue levels.
目的：抑制矿物晶体形成是异位钙化的关键步骤。血清钙磷蛋白颗粒（CPP）与慢性肾脏病（CKD）钙化倾向有关，但需要更多的知识来了解其功能、组装和组成。其他循环纳米结构，如细胞外囊泡（EVs）在血管钙化中的作用目前尚不清楚。在这里，我们研究了 GRP（富含 Gla 蛋白）与循环 CPP 和 EV 的关联，以及 CKD CPP 和 EV 在血管钙化中的作用。
方法和结果：从健康和 CKD 患者中分离出生物 CPP 和 EV，并使用超微结构、分析、分子和免疫技术对其进行比较表征。我们的结果表明，GRP 是循环 CPP 和 EV 的组成部分。CKD 5 期血清 CPP 和 EV 的特征是胎球蛋白-A 和 GRP 水平降低，而 CPPs CKD 5 期具有更高的矿化成熟度，类似于二级 CPP 颗粒。血管平滑肌细胞钙化实验表明，CKD 5 期 CPP 和 EV 被血管平滑肌细胞摄取，并通过促进细胞成骨软骨分化和炎症诱导血管钙化。用 γ-羧化 GRP 孵育 CKD 5 期 CPP 可挽救这些作用。在体外，在 γ-羧化 GRP、胎球蛋白-A 和 MGP（基质 gla 蛋白）存在的情况下，基本磷酸钙晶体的形成和成熟高度降低，并且在体内也鉴定出类似的抗矿化系统。
结论：尿毒症 CPP 和 EV 是 CKD 广泛钙化机制中的重要参与者。我们提出 cGRP 作为抑制因子在全身和组织水平上防止钙化的主要作用。
Arterioscler Thromb Vasc Biol. 2018-1-4
Arterioscler Thromb Vasc Biol. 2014-12-23
Toxins (Basel). 2020-12-21
Am J Physiol Heart Circ Physiol. 2023-4-1
Front Endocrinol (Lausanne). 2025-4-2
Mater Today Bio. 2025-2-19
Cardiovasc Res. 2024-12-4
J Extracell Biol. 2022-3-16
Int J Mol Sci. 2024-3-20
Int J Mol Sci. 2024-1-18
Zotero 插件