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.

Details

Title
Smooth muscle liver kinase B1 inhibits foam cell formation and atherosclerosis via direct phosphorylation and activation of SIRT6
Author
Deng, Qiming 1 ; Li, Hongxuan 1   VIAFID ORCID Logo  ; Yue, Xiaolin 1 ; Guo, Chenghu 1 ; Sun, Yuanyuan 1 ; Ma, Chang 1 ; Gao, Jiangang 2 ; Wu, Yue 3   VIAFID ORCID Logo  ; Du, Bin 3 ; Yang, Jianmin 1 ; Zhang, Cheng 1   VIAFID ORCID Logo  ; Zhang, Wencheng 1   VIAFID ORCID Logo 

 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) 
 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) 
 The First Affiliated Hospital of Xi’an Jiaotong University, Department of Cardiology, Xi’an, China (GRID:grid.452438.c) (ISNI:0000 0004 1760 8119) 
Pages
542
Publication year
2023
Publication date
Aug 2023
Publisher
Springer Nature B.V.
e-ISSN
20414889
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2854685849
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.