Dickkopf1 (Dkk1) Alleviates Vascular Calcification by Regulating the Degradation of Phospholipase D1 (PLD1)
Dickkopf1 (Dkk1) Alleviates Vascular Calcification by Regulating the Degradation of Phospholipase D1 (PLD1)
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DOI：
10.1007/s12265-022-10251-y
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发表时间：
2022-04-14
影响因子：
3.4
通讯作者：
Zhang, Mei
中科院分区：
文献类型：
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作者：
Li, Xuan;Liu, Xiao-lin;Zhang, Mei
血管钙化（VC）是动脉粥样硬化（AS）、慢性肾脏疾病和糖尿病患者心血管死亡率和发病率的重要危险因素。Dickkopf1（Dkk1）是一种多功能的分泌型糖蛋白，是一种潜在的抗肿瘤靶点。最近，Dkk 1被证明与AS的发展密切相关。然而，Dkk1在VC中的作用仍然难以捉摸。在这项研究中，我们探讨的作用和分子机制的Dkk1在VC的基础上，平滑肌特异性Dkk1基因敲除（Dkk1（SMKO））小鼠模型。我们的数据表明，Dkk1表达减少钙化条件下，Dkk1过表达减轻高磷酸盐诱导的血管钙化。在体内，平滑肌Dkk1特异性敲除加重了小鼠血管钙化。然而，磷脂酶D1（PLD1）过表达部分削弱了Dkk1对血管钙化的保护作用。Dkk 1通过调节自噬体的形成和成熟，促进PLD 1的降解，从而减缓血管钙化。总之，我们发现Dkk 1可以通过调节PLD 1的降解来减轻血管钙化。
Vascular calcification (VC) is a significant risk factor for cardiovascular mortality and morbidity in patients with atherosclerosis (AS), chronic kidney disease, and diabetes. Dickkopf1 (Dkk1) is a multifunctional secreted glycoprotein that has been explored as a novel potential antitumor target. Recently, Dkk1 was shown to be closely associated with AS development. However, the role of Dkk1 in VC remains elusive. In this study, we explored the role and molecular mechanisms of Dkk1 in VC based on a smooth muscle-specific Dkk1-knockout (Dkk1(SMKO)) mouse model. Our data indicated that Dkk1 expression was decreased under calcifying conditions and that Dkk1 overexpression alleviated high phosphate-induced vascular calcification. In vivo, smooth muscle Dkk1-specific knockout aggravated vascular calcification in mice. However, phospholipase D1 (PLD1) overexpression partially weakened the protective effect of Dkk1 against vascular calcification. Mechanistically, Dkk1 slowed vascular calcification by promoting the degradation of PLD1 via the regulating autophagosome formation and maturation. In conclusion, we found that Dkk1 could alleviate vascular calcification by regulating the degradation of PLD1.