National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, China.
Cell Death Dis. 2023 Aug 22;14(8):542. doi: 10.1038/s41419-023-06054-x.
Foam cell formation is a hallmark of the early phase of atherosclerosis. Growing evidence has demonstrated that vascular smooth muscle cells (VSMCs) comprise a considerable proportion of foam cells. Liver kinase B1 (LKB1) plays a crucial part in cardiovascular diseases. However, the role of LKB1 in VSMC-derived foam cell formation and atherosclerosis remains unclear. To explore the effects of LKB1 on VSMC-derived foam cell formation and atherosclerosis, we generated smooth muscle-specific LKB1 knockout (LKB1) mice by crossbreeding LKB1 mice with SM22α-CreER mice. LKB1 expression decreased in plaque-loaded aortas and oxidized low-density lipoprotein (oxLDL)-treated VSMCs. Compared with controls, atherosclerosis development was exacerbated in LKB1 mice via the promotion of VSMC-derived foam cell formation. Conversely, LKB1 overexpression inhibited lipid uptake and foam cell formation in VSMCs. Mechanistically, LKB1 binds to SIRT6 and directly phosphorylates and activates it, thereby reducing lectin-like oxLDL receptor-1 (LOX-1) via SIRT6-dependent histone deacetylation. Finally, adeno-associated virus (AAV)-mediated LOX-1 deficiency in smooth muscle ameliorated atherosclerosis in LKB1 mice. Our findings suggest that LKB1 may modulate VSMC-derived foam cell formation and atherosclerosis via the phosphorylation and activation of SIRT6.
泡沫细胞的形成是动脉粥样硬化早期阶段的一个标志。越来越多的证据表明，血管平滑肌细胞（VSMCs）构成了相当一部分泡沫细胞。肝激酶 B1（LKB1）在心血管疾病中起着至关重要的作用。然而，LKB1 在 VSMC 衍生的泡沫细胞形成和动脉粥样硬化中的作用尚不清楚。为了探讨 LKB1 对 VSMC 衍生的泡沫细胞形成和动脉粥样硬化的影响，我们通过将 LKB1 小鼠与 SM22α-CreER 小鼠杂交，生成了平滑肌特异性 LKB1 敲除（LKB1）小鼠。斑块负荷的主动脉和氧化型低密度脂蛋白（oxLDL）处理的 VSMCs 中 LKB1 的表达降低。与对照组相比，LKB1 小鼠通过促进 VSMC 衍生的泡沫细胞形成，使动脉粥样硬化的发展加剧。相反，LKB1 的过表达抑制了 VSMCs 中的脂质摄取和泡沫细胞形成。机制上，LKB1 与 SIRT6 结合，并直接磷酸化和激活它，从而通过 SIRT6 依赖性组蛋白去乙酰化来减少凝集素样 oxLDL 受体-1（LOX-1）。最后，腺相关病毒（AAV）介导的平滑肌中 LOX-1 的缺失改善了 LKB1 小鼠的动脉粥样硬化。我们的研究结果表明，LKB1 可能通过 SIRT6 的磷酸化和激活来调节 VSMC 衍生的泡沫细胞形成和动脉粥样硬化。
