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与CON组相比，HG组细胞活性明显下降（
P
< 0.01），心肌细胞和线粒体内ROS荧光强度（
P
< 0.01）、NLRP3免疫荧光强度（
P
< 0.01）以及焦亡相关因子NLRP3，GSDMD和GSDMD-NT的蛋白表达（
P
< 0.01）均明显升高，铁死亡相关因子GPX4蛋白表达下降（
P
< 0.01）。与HG组相比，HG+ MitoQ和HG+MCC950组细胞活性明显升高（
P
< 0.01），细胞和线粒体内ROS荧光强度（
P
< 0.01）、NLRP3免疫荧光强度（
P
< 0.01）以及NLRP3、GSDMD和GSDMD-NT的蛋白表达明显降低（
P
< 0.05），GPX4蛋白表达增高（
P
< 0.01）。与HG组相比，HG+ MCC950+ROT组细胞活性和NLRP3、GSDMD-NT的蛋白表达无明显差异（
P
>0.05）；但与HG+MCC950组相比，HG+MCC950+ ROT组细胞活性明显降低（
P
< 0.01），ROS荧光强度、NLRP3炎症小体免疫荧光以及NLRP3、GSDMD-NT的蛋白表达均明显升高，GPX4蛋白表达降低（
P
< 0.05）。
To observe the effect of inhibiting mitochondrial oxidative stress and NLRP3 inflammasomes on high glucose (HG)-induced pyroptosis and ferroptosis in H9C2 cardiac muscle cells and explore the possible interactions between mitochondrial reactive oxygen species (ROS) and inflammasomes.
Methods
H9C2 cells exposed to high glucose (35 mmol/L) were treated with the mitochondrial antioxidant mitoquinone (MitoQ), the NLRP3 antagonist MCC950, or both MCC950 and rotenone (a mitochondrial electron transport antagonist), and the cell viability was measured with CCK-8 assay. The cellular and mitochondrial ROS levels were measured using CellRox and Mitosox fluorescent probes, respectively. The cellular NLRP3 inflammasome level was detected with immunofluorescence assay, and the expressions of the key proteins related with pyroptosis and ferroptosis were determined with Western blotting.
Results
HG exposure significantly lowered the viability of H9C2 cells (
P
< 0.01), reduced the expression of GPX4 protein (a key protein related with ferroptosis) (
P
< 0.01), and increased the fluorescence intensities of NLRP3 (
P
< 0.01) and ROS (at both the cellular and mitochondrial levels,
P
< 0.01) and the protein expressions of NLRP3 and GSDMD-NT (
P
< 0.01). Treatment with either MitoQ or MCC950 significantly increased the viability of HG-exposed cells (
P
< 0.01), increased GPX4 expression (
P
< 0.01), and reduced the fluorescence intensities of NLRP3 (
P
< 0.01) and cellular and mitochondrial ROS (
P
< 0.01) and the protein expressions of NLRP3 and GSDMD-NT (
P
< 0.05). Compared with MCC950 treatment, treatment with both MCC950 and rotenone significantly reduced the viability of HG-exposed cells (
P
< 0.01), lowered GPX4 expression (
P
< 0.01), and increased the fluorescence intensities of ROS and NLRP3 (
P
< 0.01) and the protein levels of NLRP3 and GSDMD-NT (
P
< 0.05).
Conclusion
MitoQ inhibits mitochondrial ROS production to reduce HGinduced NLRP3 inflammasome activation and thus suppress pyroptosis and ferroptosis of cardiac muscle cells. There may be an interaction between mitochondrial ROS and NLRP3 inflammasomes.
采用SPSS 24.0统计软件，计量资料以均数±标准差表示，多组间比较采用单因素方差分析，并用Tukey检验进行组间比较。
P
< 0.05时认为差异有统计学意义。
2. 结果
2.1. 细胞活性变化
2.1.1. 药物浓度确定
CCK-8结果显示，H9C2心肌细胞干预24 h后，与CON组相比，HG组细胞活性明显下降（
P
=0.003）。与HG组相比，MitoQ终浓度为0.1、0.5、1 μmol/mL的HG+MitoQ组活性均明显升高（
P
=0.002;
P
< 0.001;
P
=0.001），其中0.5 μmol/mL组活性最高（
图 1A
）。与CON组相比，随着ROT浓度升高，细胞活性逐渐下降（
P
< 0.001）；1 μmol/mL时细胞状态不佳，故选取0.5 μmol/mL的MitoQ和ROT进行实验（
图 1B
）。
Viability of H9C2 cardiac muscle cells treated with different concentrations of mitoquinone (
A
), rotenone (ROT;
B
) or both (
C
). Data are presented as
Mean
±
SD
(
n
=5 or 4).
**
P
< 0.01,
***
P
< 0.001
vs
CON;
##
P
< 0.01,
###
P
< 0.001
vs
HG;
&&
P
< 0.01
vs
HG+MCC950.
2.1.2. 各组细胞活性变化
CCK-8结果显示，与CON组相比，HG组细胞活性明显下降（
P
=0.005）。与HG组相比，HG+MitoQ和HG+MCC950组活性明显升高（
P
=0.008;
P
< 0.001）。HG+MCC50+ROT组细胞活性与HG组相比无明显变化（
P
=0.976），与HG+MCC950组相比明显降低（
P
=0.001，
图 1C
）。
2.2. 各组细胞和线粒体内ROS水平的变化
如
图 2
所示，与CON组相比，HG组反映胞浆氧自由基变化的CellRox（绿色，
图 2A
）和反映线粒体氧自由基变化的MitoSox（红色，
图 2B
）平均荧光强度明显增强（
P
< 0.001）。与HG组相比，HG+MitoQ（
P
=0.004;
P
< 0.001）和HG+MCC950（
P
< 0.001）组荧光强度均明显下降；同时与HG+MCC950组相比，HG+MCC50+ROT组CellRox和MitoSox荧光强度也明显增强（
P
=0.008;
P
=0.016）。
Fluorescence staining of H9C2 cells with CellRox and MitoSox.
A
,
B
: Images of CellRox (green; scale bar=100 μm) and MitoSox (red; scale bar=20 μm) and DAPI (blue) fluorescence staining.
C
,
D
: Quantitative analysis of fluorescence intensity of CellRox and MitoSox staining (
Mean
±
SD
,
n
=5).
***
P
< 0.001
vs
CON;
##
P
< 0.01,
###
P
< 0.001
vs
HG;
&
P
< 0.05,
&&
P
< 0.01
vs
HG+ MCC950.
2.3. 各组心肌细胞NLRP3免疫荧光变化
与CON组相比，HG组红色荧光强度明显增强（
P
< 0.001）。与HG组相比，HG+MitoQ、HG+MCC950组红色荧光强度明显下降（
P
< 0.001;
P
=0.003）。与HG+MCC950组相比，HG+MCC50+ROT组NLRP3荧光强度也明显增强（
P
=0.034，
图 3
）。
Immunofluorescence staining of NLRP3 in H9C2 cells.
A
: Images of NLRP3 (red) and DAPI (blue) immunofluorescence staining (× 200, scale bar=50 μm).
B
: Quantitative analysis of NLRP3 fluorescence intensity (
Mean
±
SD
,
n
=5).
***
P
< 0.001
vs
CON;
##
P
< 0.01,
###
P
< 0.001
vs
HG;
&
P
< 0.05
vs
HG+MCC950.
2.4. 各组心肌细胞内NLRP3、GSDMD、GSDMD-NT和GPX4蛋白表达变化
Western blot结果显示，与CON组相比，HG组NLRP3及焦亡相关因子GSDMD和GSDMD-NT蛋白表达均明显升高（
P
=0.010;
P
=0.003;
P
< 0.001），GPX4蛋白明显降低（
P
< 0.001）。与HG组相比，HG+MitoQ和HG + MCC950组NLRP3（
P
=0.020;
P
=0.018）、GSDMD（
P
=0.001;
P
=0.002）和GSDMD-NT（
P
< 0.001;
P
=0.001）蛋白表达均明显下降，GPX4蛋白表达明显上升（
P
=0.002;
P
=0.003）。与HG组相比，HG+MCC950+ ROT组NLRP3（
P
=0.873）和GSDMD-NT（
P
=0.202）蛋白表达无明显变化，GSDMD降低（
P
=0.001）；与HG+ MCC950组相比，HG + MCC950 + ROT组NLRP3和GSDMD-NT蛋白表达明显上升（
P
=0.024;
P
=0.033），GPX4蛋白表达下降（
P
=0.032，
图 4
）。
Changes of protein levels in each group.
A
,
B
: Western blots of NLRP3, GSDMD, GSDMD-NT, GPX4 and GAPDH in H9C2 cells.
C
-
F
: NLRP3, GSDMD, GSDMD-NT and GPX4 protein levels normalized by GAPDH levels (
Mean
±
SD
,
n
=5).
*
P
< 0.05,
**
P
< 0.01,
***
P
< 0.001
vs
CON;
#
P
< 0.05,
##
P
< 0.01,
###
P
< 0.001
vs
HG;
&
P
< 0.05
vs
HG+MCC950.
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