Bäck Magnus, Aranyi Tamas, Cancela M Leonor, Carracedo Miguel, Conceição Natércia, Leftheriotis Georges, Macrae Vicky, Martin Ludovic, Nitschke Yvonne, Pasch Andreas, Quaglino Daniela, Rutsch Frank, Shanahan Catherine, Sorribas Victor, Szeri Flora, Valdivielso Pedro, Vanakker Olivier, Kempf Hervé
Translational Cardiology, Center for Molecular Medicine, Karolinska University Hospital Stockholmt, Stockholm, Sweden.
Research Center for Natural Sciences, Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary.
Front Cardiovasc Med. 2019 Jan 18;5:196. doi: 10.3389/fcvm.2018.00196. eCollection 2018.
The physicochemical deposition of calcium-phosphate in the arterial wall is prevented by calcification inhibitors. Studies in cohorts of patients with rare genetic diseases have shed light on the consequences of loss-of-function mutations for different calcification inhibitors, and genetic targeting of these pathways in mice have generated a clearer picture on the mechanisms involved. For example, generalized arterial calcification of infancy (GACI) is caused by mutations in the enzyme ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (eNPP1), preventing the hydrolysis of ATP into pyrophosphate (PP). The importance of PP for inhibiting arterial calcification has been reinforced by the protective effects of PP in various mouse models displaying ectopic calcifications. Besides PP, Matrix Gla Protein (MGP) has been shown to be another potent calcification inhibitor as Keutel patients carrying a mutation in the encoding gene or -deficient mice develop spontaneous calcification of the arterial media. Whereas PP and MGP represent locally produced calcification inhibitors, also systemic factors contribute to protection against arterial calcification. One such example is Fetuin-A, which is mainly produced in the liver and which forms calciprotein particles (CPPs), inhibiting growth of calcium-phosphate crystals in the blood and thereby preventing their soft tissue deposition. Other calcification inhibitors with potential importance for arterial calcification include osteoprotegerin, osteopontin, and klotho. The aim of the present review is to outline the latest insights into how different calcification inhibitors prevent arterial calcification both under physiological conditions and in the case of disturbed calcium-phosphate balance, and to provide a consensus statement on their potential therapeutic role for arterial calcification.
钙化抑制剂可防止磷酸钙在动脉壁的物理化学沉积。对患有罕见遗传病患者队列的研究揭示了不同钙化抑制剂功能丧失突变的后果，在小鼠中对这些途径进行基因靶向研究，使所涉及的机制更加清晰。例如，婴儿期全身性动脉钙化（GACI）是由胞外核苷酸焦磷酸酶/磷酸二酯酶-1（eNPP1）酶的突变引起的，该突变阻止了ATP水解为焦磷酸（PP）。PP在各种显示异位钙化的小鼠模型中的保护作用，强化了PP对抑制动脉钙化的重要性。除了PP，基质Gla蛋白（MGP）已被证明是另一种有效的钙化抑制剂——因为携带编码基因突变的Keutel患者或基因缺陷小鼠会出现动脉中层的自发性钙化。虽然PP和MGP代表局部产生的钙化抑制剂，但全身因素也有助于预防动脉钙化。其中一个例子是胎球蛋白-A，它主要在肝脏中产生，并形成钙蛋白颗粒（CPPs），抑制血液中磷酸钙晶体的生长，从而防止它们在软组织中沉积。其他对动脉钙化可能具有重要意义的钙化抑制剂包括骨保护素、骨桥蛋白和klotho。本综述的目的是概述关于不同钙化抑制剂在生理条件下以及在磷酸钙平衡紊乱情况下如何预防动脉钙化的最新见解，并就它们对动脉钙化的潜在治疗作用提供一份共识声明。
