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Abstract
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 (LKB1SMKO) mice by crossbreeding LKB1flox/flox mice with SM22α-CreERT2 mice. LKB1 expression decreased in plaque-loaded aortas and oxidized low-density lipoprotein (oxLDL)-treated VSMCs. Compared with controls, atherosclerosis development was exacerbated in LKB1SMKO 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 LKB1SMKO mice. Our findings suggest that LKB1 may modulate VSMC-derived foam cell formation and atherosclerosis via the phosphorylation and activation of SIRT6.
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1 Qilu Hospital of Shandong University, 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, Jinan, China (GRID:grid.452402.5) (ISNI:0000 0004 1808 3430)
2 Shandong University, School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Jinan, China (GRID:grid.27255.37) (ISNI:0000 0004 1761 1174)
3 The First Affiliated Hospital of Xi’an Jiaotong University, Department of Cardiology, Xi’an, China (GRID:grid.452438.c) (ISNI:0000 0004 1760 8119)