Introduction: Hyperuricemia may be involved in the phenotypic transformation of vascular smooth muscle cells, thus promoting the occurrence of atherosclerosis, and autophagy may be one of the important links, but little is known about the specific molecular mechanism. Methods: We established a mouse model of hyperuricemia and studied the relationship between changes in autophagy levels and the phenotypic transformation of muscle cells. Results: Our study found that high uric acid levels promote the phenotypic transformation of muscle cells by inhibiting autophagy, thus enhancing their proliferation and migration abilities. If autophagy is restored, phenotypic transformation can be reversed by reducing the levels of the transcription factor Kruppel-like factor 4. Conclusion: Uric acid may induce the phenotypic transformation of muscle cells and promote the occurrence of atherosclerosis by disrupting normal autophagy.

1.
Jayachandran
M
,
Qu
S
.
Harnessing hyperuricemia to atherosclerosis and understanding its mechanistic dependence
.
Med Res Rev
.
2021
;
41
(
1
):
616
29
.
2.
Krishnan
E
,
Pandya
BJ
,
Chung
L
,
Dabbous
O
.
Hyperuricemia and the risk for subclinical coronary atherosclerosis: data from a prospective observational cohort study
.
Arthritis Res Ther
.
2011
13
2
R66
.
3.
Liu
YX
,
Yuan
PZ
,
Wu
JH
,
Hu
B
.
Lipid accumulation and novel insight into vascular smooth muscle cells in atherosclerosis
.
J Mol Med
.
2021
;
99
(
11
):
1511
26
.
4.
Maruhashi
T
,
Hisatome
I
,
Kihara
Y
,
Higashi
Y
.
Hyperuricemia and endothelial function: from molecular background to clinical perspectives
.
Atherosclerosis
.
2018
;
278
:
226
31
.
5.
Kimura
Y
,
Tsukui
D
,
Kono
H
.
Uric acid in inflammation and the pathogenesis of atherosclerosis
.
Int J Mol Sci
.
2021
;
22
(
22
):
12394
.
6.
Lee
TS
,
Lu
TM
,
Chen
CH
,
Guo
BC
,
Hsu
CP
.
Hyperuricemia induces endothelial dysfunction and accelerates atherosclerosis by disturbing the asymmetric dimethylarginine/dimethylarginine dimethylaminotransferase 2 pathway
.
Redox Biol
.
2021
;
46
:
102108
.
7.
Yu
W
,
Liu
W
,
Xie
D
,
Wang
Q
,
Xu
C
,
Zhao
H
.
High level of uric acid promotes atherosclerosis by targeting NRF2-mediated autophagy dysfunction and ferroptosis
.
Oxid Med Cell Longev
.
2022
;
2022
:
9304383
.
8.
Ni
T
,
Gao
F
,
Zhang
J
,
Lin
H
,
Luo
H
,
Chi
J
.
Impaired autophagy mediates hyperhomocysteinemia-induced HA-VSMC phenotypic switching
.
J Mol Histol
.
2019
;
50
(
4
):
305
14
.
9.
Tang
L
,
Xu
Y
,
Wei
Y
,
He
X
.
Uric acid induces the expression of TNF-α via the ROS-MAPK-NF-κB signaling pathway in rat vascular smooth muscle cells
.
Mol Med Rep
.
2017
;
16
(
5
):
6928
33
.
10.
Liu
T
,
Zhang
L
,
Joo
D
,
Sun
SC
.
NF-κB signaling in inflammation
.
Signal Transduct Target Ther
.
2017
;
2
:
17023
.
11.
Yap
C
,
Mieremet
A
,
de Vries
CJM
,
Micha
D
,
de Waard
V
.
Six shades of vascular smooth muscle cells illuminated by KLF4 (Krüppel-Like factor 4)
.
Arterioscler Thromb Vasc Biol
.
2021
;
41
(
11
):
2693
707
.
12.
Grootaert
MOJ
,
Moulis
M
,
Roth
L
,
Martinet
W
,
Vindis
C
,
Bennett
MR
.
Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis
.
Cardiovasc Res
.
2018
;
114
(
4
):
622
34
.
13.
Osonoi
Y
,
Mita
T
,
Azuma
K
,
Nakajima
K
,
Masuyama
A
,
Goto
H
.
Defective autophagy in vascular smooth muscle cells enhances cell death and atherosclerosis
.
Autophagy
.
2018
;
14
(
11
):
1991
2006
.
14.
Lin
X
,
Ouyang
S
,
Zhi
C
,
Li
P
,
Tan
X
,
Ma
W
.
Focus on ferroptosis, pyroptosis, apoptosis and autophagy of vascular endothelial cells to the strategic targets for the treatment of atherosclerosis
.
Arch Biochem Biophys
.
2022
;
715
:
109098
.
15.
Brenner
DA
,
Alcorn
JM
,
Feitelberg
SP
,
Leffert
HL
,
Chojkier
M
.
Expression of collagen genes in the liver
.
Mol Biol Med
.
1990
;
7
(
2
):
105
15
.
16.
Liu
D
,
Cui
W
,
Liu
B
,
Hu
H
,
Liu
J
,
Xie
R
.
Atorvastatin protects vascular smooth muscle cells from TGF-β1-stimulated calcification by inducing autophagy via suppression of the β-catenin pathway
.
Cell Physiol Biochem
.
2014
;
33
(
1
):
129
41
.
17.
Blum
A
,
Mostow
K
,
Jackett
K
,
Kelty
E
,
Dakpa
T
,
Ryan
C
.
KLF4 regulates metabolic homeostasis in response to stress
.
Cells
.
2021
;
10
(
4
):
830
.
18.
Zhang
X
,
Zheng
B
,
Zhao
L
,
Shen
J
,
Yang
Z
,
Zhang
Y
.
KLF4-PFKFB3-driven glycolysis is essential for phenotypic switching of vascular smooth muscle cells
.
Commun Biol
.
2022
;
5
(
1
):
1332
.
19.
Tong
J
,
Ji
B
,
Gao
YH
,
Lin
H
,
Ping
F
,
Chen
F
.
Sirt6 regulates autophagy in AGE-treated endothelial cells via KLF4
.
Nutr Metabol Cardiovasc Dis
.
2022
;
32
(
3
):
755
64
.
20.
Wang
X
,
Su
W
,
Ma
M
,
Zhu
L
,
Gao
R
,
Qin
C
.
The KLF4-p62 axis prevents vascular endothelial cell injury via the mTOR/S6K pathway and autophagy in diabetic kidney disease
.
Endokrynol Pol
.
2022
;
73
(
5
):
837
45
.
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