血管钙化(VC)是动脉粥样硬化(AS)患者心血管死亡率和发病率的重要危险因素,慢性肾病,和糖尿病。Dickkopf1(Dkk1)是一种多功能分泌型糖蛋白,已被开发为新的潜在抗肿瘤靶标。最近,Dkk1与AS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,我们基于平滑肌特异性Dkk1敲除(Dkk1SMKO)小鼠模型,探讨了Dkk1在VC中的作用和分子机制。我们的数据表明Dkk1表达在钙化条件下降低,Dkk1过表达减轻了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。机械上,Dkk1通过调节自噬体的形成和成熟,促进PLD1的降解,从而减缓血管钙化。总之,我们发现Dkk1可以通过调节PLD1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 (Dkk1SMKO) 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.