SFRP5（分泌型卷曲相关蛋白 5）对 WNT5A（无翅型 Wnt 家族成员 5A）诱导的内皮功能障碍的影响及其与人体动脉僵硬度的相关性。

Effect of SFRP5 (Secreted Frizzled-Related Protein 5) on the WNT5A (Wingless-Type Family Member 5A)-Induced Endothelial Dysfunction and Its Relevance With Arterial Stiffness in Human Subjects.

机构信息

From the Department of Internal Medicine (Y.K.C., Y.M.K., S.E.L., W.J.L., J.-Y.P., C.H.J.).

Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea (Y.K.C.).

出版信息

Arterioscler Thromb Vasc Biol. 2018 Jun;38(6):1358-1367. doi: 10.1161/ATVBAHA.117.310649. Epub 2018 Apr 19.

DOI:10.1161/ATVBAHA.117.310649

PMID:29674475

Abstract

OBJECTIVE

SFRP5 (secreted frizzled-related protein 5) is an endogenous inhibitor of WNT5A (wingless-type family member 5a), which has been implicated in atherosclerosis. However, contradictory results have been reported about the role of SFRP5 in atherosclerosis. We aimed to investigate whether SFRP5 could restore WNT5A-induced endothelial dysfunction in vitro and ex vivo. In addition, we sought to determine whether the serum concentration of SFRP5 is associated with atherosclerosis in humans.

APPROACH AND RESULTS

We measured endothelium-dependent vasorelaxation in the isolated thoracic aorta of Sprague-Dawley rats. In addition, we measured intracellular nitric oxide (NO) in human endothelial cells. The protein abundance of total and phosphorylated JNK (c-Jun N-terminal kinase), AKT (protein kinase B), and endothelial NO synthase was analyzed in human endothelial cells. Circulating SFRP5 and WNT5A levels and brachial-ankle pulse wave velocity were measured in 282 human subjects with type 2 diabetes mellitus. SFRP5 dose dependently restored Wnt5-induced impaired vasorelaxation in rat thoracic aorta by an endothelial NO synthase-dependent mechanism. SFRP5 treatment restored the WNT5A-induced reduction of NO production via endothelial NO synthase in human endothelial cells. WNT5A-induced changes in the phosphorylation of JNK, AKT, and endothelial NO synthase were ameliorated with SFRP5 administration. In humans with type 2 diabetes mellitus, the serum SFRP5 concentration positively correlated with brachial-ankle pulse wave velocity (=0.146; =0.024). Multivariate linear regression analysis demonstrated that the serum SFRP5 concentration was independently associated with brachial-ankle pulse wave velocity after adjustment for potential confounders [ (SE)=7.40 (3.35); =0.028].

CONCLUSIONS

Our data suggest the possible compensatory action of SFRP5 against atherosclerosis under conditions of metabolic dysfunction.

摘要

目的

分泌型卷曲相关蛋白 5（secreted frizzled-related protein 5，SFRP5）是 WNT5A（无翅型 WNT 家族成员 5a）的内源性抑制剂，其与动脉粥样硬化有关。然而，关于 SFRP5 在动脉粥样硬化中的作用，已有相互矛盾的结果报道。本研究旨在探讨 SFRP5 是否能恢复体外和体内 WNT5A 诱导的内皮功能障碍。此外，我们还试图确定 SFRP5 的血清浓度是否与人类的动脉粥样硬化有关。

方法和结果

我们测量了 Sprague-Dawley 大鼠离体胸主动脉的内皮依赖性血管舒张功能。此外，我们还测量了人内皮细胞中的细胞内一氧化氮（NO）。分析了人内皮细胞中总蛋白和磷酸化 JNK（c-Jun N 端激酶）、AKT（蛋白激酶 B）和内皮型一氧化氮合酶的蛋白丰度。在 282 例 2 型糖尿病患者中测量了循环 SFRP5 和 WNT5A 水平以及肱踝脉搏波速度。SFRP5 呈剂量依赖性地通过内皮型一氧化氮合酶依赖的机制恢复 Wnt5 诱导的大鼠胸主动脉舒张功能障碍。SFRP5 治疗可通过内皮型一氧化氮合酶恢复 WNT5A 诱导的 NO 产生减少。SFRP5 给药可改善 WNT5A 诱导的 JNK、AKT 和内皮型一氧化氮合酶磷酸化的变化。在 2 型糖尿病患者中，血清 SFRP5 浓度与肱踝脉搏波速度呈正相关（r=0.146，P=0.024）。多元线性回归分析表明，在校正潜在混杂因素后，血清 SFRP5 浓度与肱踝脉搏波速度独立相关[β（SE）=7.40（3.35）；P=0.028]。