Division of Renal Medicine and Baxter Novum, Karolinska Institutet, Karolinska University Hospital, SE-14186 Stockholm, Sweden.
Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, SE-58185 Linköping, Sweden.
Nat Rev Nephrol. 2017 Jul;13(7):429-442. doi: 10.1038/nrneph.2017.60. Epub 2017 May 15.
Cardiovascular disease is the main cause of early death in the settings of chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and ageing. Cardiovascular events can be caused by an imbalance between promoters and inhibitors of mineralization, which leads to vascular calcification. This process is akin to skeletal mineralization, which is carefully regulated and in which isozymes of alkaline phosphatase (ALP) have a crucial role. Four genes encode ALP isozymes in humans. Intestinal, placental and germ cell ALPs are tissue-specific, whereas the tissue-nonspecific isozyme of ALP (TNALP) is present in several tissues, including bone, liver and kidney. TNALP has a pivotal role in bone calcification. Experimental overexpression of TNALP in the vasculature is sufficient to induce vascular calcification, cardiac hypertrophy and premature death, mimicking the cardiovascular phenotype often found in CKD and T2DM. Intestinal ALP contributes to the gut mucosal defence and intestinal and liver ALPs might contribute to the acute inflammatory response to endogenous or pathogenic stimuli. Here we review novel mechanisms that link ALP to vascular calcification, inflammation, and endothelial dysfunction in kidney and cardiovascular diseases. We also discuss new drugs that target ALP, which have the potential to improve cardiovascular outcomes without inhibiting skeletal mineralization.
心血管疾病是慢性肾脏病（CKD）、2 型糖尿病（T2DM）和衰老患者早期死亡的主要原因。心血管事件可能是由矿化促进剂和抑制剂之间的失衡引起的，这会导致血管钙化。这个过程类似于骨骼矿化，后者受到严格调控，碱性磷酸酶（ALP）同工酶在其中起着关键作用。人类有 4 个基因编码 ALP 同工酶。肠、胎盘和生殖细胞 ALP 是组织特异性的，而组织非特异性 ALP（TNALP）同工酶存在于包括骨骼、肝脏和肾脏在内的多种组织中。TNALP 在骨骼钙化中起着关键作用。在血管中过度表达 TNALP 足以诱导血管钙化、心脏肥大和过早死亡，模拟 CKD 和 T2DM 中经常发现的心血管表型。肠 ALP 有助于肠道黏膜防御，而肠道和肝脏 ALP 可能有助于对内源或致病刺激的急性炎症反应。在这里，我们综述了将 ALP 与肾脏和心血管疾病中的血管钙化、炎症和内皮功能障碍联系起来的新机制。我们还讨论了靶向 ALP 的新药，这些药物有可能改善心血管结局而不抑制骨骼矿化。
