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 of Shandong University, Jinan, China.
Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China.
J Mol Cell Cardiol. 2020 May;142:39-52. doi: 10.1016/j.yjmcc.2020.03.017. Epub 2020 Apr 5.
Vascular calcification is a pathological process closely related to atherosclerosis, diabetic vascular diseases, vascular injury, hypertension, chronic kidney disease and aging. Lethal giant larvae 1 (LGL1) is known as a key regulator of cell polarity and plays an important role in tumorigenesis. However, whether LGL1 regulates vascular calcification remains unclear. In this study, we generated smooth muscle-specific LGL1 knockout (LGL1) mice by cross-breeding LGL1 mice with α-SMA-Cre mice. LGL1 level was significantly decreased during calcifying conditions. Overexpression of LGL1 restrained high phosphate-induced calcification in vascular smooth muscle cells (VSMCs). Mechanically, LGL1 could bind with high mobility group box 1 (HMGB1) and promote its degradation via the lysosomal pathway, thereby inhibiting calcification. Smooth muscle-specific deletion of LGL1 increased HMGB1 level and aggravated vitamin D3-induced vascular calcification, which was attenuated by an HMGB1 inhibitor. LGL1 may inhibit vascular calcification by preventing osteogenic differentiation via promoting HMGB1 degradation.
血管钙化是一种与动脉粥样硬化、糖尿病血管疾病、血管损伤、高血压、慢性肾病和衰老密切相关的病理过程。致死性巨大幼虫 1（LGL1）被认为是细胞极性的关键调节因子，在肿瘤发生中发挥重要作用。然而，LGL1 是否调节血管钙化尚不清楚。在这项研究中，我们通过将 LGL1 小鼠与α-SMA-Cre 小鼠杂交，产生了平滑肌特异性 LGL1 敲除（LGL1）小鼠。在钙化条件下，LGL1 水平显著降低。过表达 LGL1 抑制了高磷诱导的血管平滑肌细胞（VSMCs）钙化。在机制上，LGL1 可以与高迁移率族蛋白 B1（HMGB1）结合，并通过溶酶体途径促进其降解，从而抑制钙化。平滑肌特异性 LGL1 缺失增加了 HMGB1 水平，并加重了维生素 D3 诱导的血管钙化，而 HMGB1 抑制剂则减轻了这种作用。LGL1 可能通过促进 HMGB1 降解来抑制血管钙化，从而阻止成骨分化。
