The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107, Wen Hua Xi Road, Jinan, 250012, Shandong, China.
J Cardiovasc Transl Res. 2022 Dec;15(6):1327-1339. doi: 10.1007/s12265-022-10251-y. Epub 2022 Apr 14.
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) 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.
血管钙化 (VC) 是动脉粥样硬化 (AS)、慢性肾脏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) 是一种多功能分泌糖蛋白，已被探索作为一种新的潜在抗肿瘤靶标。最近，Dkk1 被证明与 AS 的发展密切相关。然而，Dkk1 在 VC 中的作用仍不清楚。在这项研究中，我们基于平滑肌特异性 Dkk1 敲除 (Dkk1) 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，在钙化条件下 Dkk1 的表达减少，Dkk1 过表达减轻高磷诱导的血管钙化。在体内，平滑肌 Dkk1 特异性敲除加重了小鼠的血管钙化。然而，磷脂酶 D1 (PLD1) 的过表达部分削弱了 Dkk1 对血管钙化的保护作用。在机制上，Dkk1 通过调节自噬体的形成和成熟来促进 PLD1 的降解，从而减缓血管钙化。总之，我们发现 Dkk1 通过调节 PLD1 的降解来减轻血管钙化。
