黄芪总黄酮通过调控miR-190a-5p对缺氧/复氧诱导的心肌细胞损伤的影响

doi:10.3877/cma.j.issn.2095-1221.2022.06.004

目的

探讨黄芪总黄酮（TFA）对缺氧/复氧（H/R）诱导心肌细胞损伤的影响及其可能作用机制。

方法

空白培养H9c2细胞记为对照组，H9c2细胞放入缺氧培养箱内（37℃、95%N₂、5%CO₂） 4 h，更换培养基，放入正常培养箱内复氧处理12 h，记为H/R组；50、100、150 μg/mL TFA培养H9c2细胞24 h后进行H/R处理，记为H/R+TFA-L组、H/ R+TFA-M组、H/R+TFA-H组。miR-NC、miR-190a-5p mimics分别转染至H9c2细胞后进行H/ R处理，记为H/R+miR-NC组、H/R+miR-190a-5p组；anti-miR-NC、anti-miR-190a- 5p分别转染至H9c2细胞后用150 μg/mL TFA培养H9c2细胞24 h，并进行H/R处理，记为H/R+ TFA-H+anti-miR-NC组、H/R+TFA-H+anti-miR-190a-5p组。RT-PCR检测miR-190a-5p表达量；采用流式细胞术检测细胞凋亡率；试剂盒检测SOD、MDA、LDH和ROS水平；Western blot检测cleaved caspase-3、BCL2蛋白表达量。两组间比较采用独立样本t检验，多组间比较采用单因素方差分析。

结果

与对照比较，H/R组细胞凋亡率[（32.76±2.42）%比（3.23±0.43）%]、cleaved caspase-3 （0.83±0.05比0.26±0.02）、MDA[（23.36±2.25）比（4.26±0.48）nmol/mg]、LDH [（52.51±3.82）比（13.66±1.72）U/L]、ROS[（192.63±10.42）%比（98.51±6.55）%]水平增高（P均< 0.05），BCL2蛋白水平（0.33±0.06比0.91±0.05）、SOD [（52.14±4.95）比（135.32±9.22）U/mg]水平、miR-190a-5p表达量（0.32±0.05比1.02±0.10）降低（P均< 0.05）；与H/R组比较，H/R+TFA-L组、H/R+TFA-M组、H/R+TFA-H组细胞凋亡率[（27.09±2.11）%、（19.21±1.59）%、（11.01±1.25）%比（32.76±2.42）%]、cleaved caspase-3、MDA [（18.17± 1.67）、（14.08±1.22）、（9.84±0.73）比（23.36±2.25）nmol/mg]、LDH [（43.11±4.30）、（31.25± 2.59）、（19.42±1.89）比（52.51±3.82） U/L]、ROS水平[（166.11±9.88）%、（141.52±8.94）%、（115.32±7.55）%比（192.63±10.42）%]降低（P均< 0.05），BCL2蛋白水平、SOD [（72.33± 5.87）、（92.08±6.27）、（116.38±7.66）比（52.14±4.95）U/mg]水平、miR-190a-5p表达量升高（P < 0.05），且呈浓度依赖性；与H/R+miR-NC组比较，H/R+miR-190a-5p组细胞凋亡率[（13.51± 1.65）%比（33.07±2.52）%]、cleaved caspase-3、MDA [（13.15±1.67）比（24.08± 3.24） nmol/ mg]、LDH [（29.48±2.55）比（50.68±4.83） U/L）]、ROS [（132.14±9.47）%比（180.11± 12.45）%]水平降低（P均< 0.05），BCL2蛋白水平、SOD [（85.64±6.11）比（51.27± 4.98）U/mg]水平升高（P均< 0.05）；转染anti-miR-190a-5p可减低TFA对H/R诱导的H9c2细胞凋亡、氧化应激的作用。

结论

TFA可通过上调miR-190a-5p表达而抑制细胞凋亡、氧化应激从而减轻H/R诱导的H9c2细胞损伤。

关键词: 黄芪总黄酮, miR-190a-5p, 缺氧/复氧, 心肌细胞H9c2, 大鼠, 细胞凋亡

Objective

To investigate the effect of total flavonids of astragalus (TFA) on hypoxia/reoxygenation (H/R) -induced cardiomyocyte injury and its possible mechanism.

Methods

Rat cardiomyocytes H9c2 were divided into a Control group (blank culture) , H/R group (hypoxia/reoxygenation treatment) , H/R+TFA-L group (TFA concentration 50 μg/mL treatment, H/R treatment) , H/R+TFA-M group (TFA concentration of 100 μg/mL treatment, H/R treatment) , H/ R+TFA-H group (TFA concentration of 150 μg/mL treatment, H/R treatment) , H/R+miR-NC group (transfected with miR-NC, H/R treatment) , H/R+miR-190a-5p group (transfected with miR-190a-5p and treated with H/R) , H/R+TFA-H+anti-miR-NC group (transfected with anti-miR-NC, TFA concentration of 100 μg/mL treatment, H/R treatment) , H/R+TFA-H+anti-miR-190a-5p group (transfected with anti-miR-190a-5p, treated with TFA concentration of 100 μg/mL, and performed H/ R treatment) . RT-PCR detection of miR-190a-5p expression; the apoptosis rate was detected by flow cytometry. The kit was used to detect the levels of SOD, MDA, ROS and LDH. Western blot was used to detect the expression of the cleaved caspase-3 protein.

Results

Compared with the Control group, the apoptosis rate of H/R group [ (32.76±2.42) %vs (3.23±0.43) %], cleaved caspase-3 (0.83± 0.05 vs 0.26±0.02) , MDA[ (23.36±2.25) vs (4.26±0.48) nmol/mg], LDH [ (52.51±3.82) vs (13.66±1.72) U/L], ROS [ (192.63±10.42) %vs (98.51±6.55) %] level increased (P < 0.05) , BCL2 protein level (0.33±0.06 vs 0.91±0.05) , SOD [ (52.14±4.95) vs (135.32±9.22) U/mg] level, miR-190a-5p expression (0.32 ± 0.05 vs 1.02 ± 0.10) decreased (P < 0.05) ; compared with H/R group, H/R+TFA-L group, H/R+TFA-M group, H/R+TFA-H group cell apoptosis rate [ (27.09± 2.11) %, (19.21±1.59) %, (11.01±1.25) %vs (32.76±2.42) %], cleaved caspase-3, MDA [ (18.17±1.67) , (14.08±1.22) , (9.84±0.73) vs (23.36±2.25) nmol/ mg], LDH [ (43.11± 4.30) , (31.25±2.59) , (19.42±1.89) vs (52.51 ± 3.82) U/L], ROS [ (166.11± 9.88) %, (141.52±8.94) %, (115.32±7.55) %vs (192.63±10.42) %] level decreased (P < 0.05) , BCL2 protein levels, SOD [ (72.33±5.87) , (92.08±6.27) , (116.38±7.66) vs (52.14± 4.95) U/ mg] level and miR-190a-5p expression increased (P < 0.05) ; compared with H/ R+ miR-NC group, the apoptosis rate [ (13.51±1.65) %vs (33.07±2.52) %], cleaved caspase-3, MDA [ (13.15± 1.67) nmol/mg vs (24.08±3.24) nmol/mg], LDH [ (29.48±2.55) vs (50.68± 4.83) U/ L], ROS [ (132.14±9.47) %vs (180.11±12.45) %] levels in H/R+miR-190a-5p group decreased (P < 0.05) , BCL2 protein levels, SOD [ (85.64±6.11) vs (51.27±4.98) U/mg] level increased (P < 0.05) . Transfection of anti-miR-190a-5p could reduce the effect of TFA on H/R-induced apoptosis and oxidative stress in H9c2 cells.

Conclusion

TFA could inhibit apoptosis and oxidative stress by up-regulating the expression of miR-190a-5p, thereby reducing H/R-induced H9c2 cell damage.

Key words: Total flavonids of astragalus, miR-190a-5p, Hypoxia/reoxygenation, Cardiomyocytes H9c2, Rat, Apoptosis

表1 引物序列信息

基因	序列（5'-3'）	预期扩增产物长度（bp）
miR-190a-5p	上游GCAGGCCTCTGTGTGATATGT	236
	下游GGCAAGACACTGTAGGAATATGT
U6	上游ATTGGAACGATACAGAGAAGATT	218
	下游GGAACGCTTCACGAATTTG

表1 引物序列信息

基因	序列（5'-3'）	预期扩增产物长度（bp）
miR-190a-5p	上游GCAGGCCTCTGTGTGATATGT	236
	下游GGCAAGACACTGTAGGAATATGT
U6	上游ATTGGAACGATACAGAGAAGATT	218
	下游GGAACGCTTCACGAATTTG

表2 黄芪总黄酮对缺氧/复氧诱导的心肌细胞凋亡影响（ ± s, n = 3）

分组	凋亡率（%）	cleaved caspase-3	BCL2
对照	3.23±0.43	0.26±0.02	0.91±0.05
H/R	32.76±2.42^a	0.83±0.05^a	0.33±0.06^a
H/R+TFA-L	27.09±2.11^ab	0.71±0.06^ab	0.48±0.05^ab
H/R+TFA-M	19.21±1.59^abc	0.57±0.04^abc	0.65±0.05^abc
H/R+TFA-H	11.01±1.25^bcd	0.42±0.04^abcd	0.81±0.06^bcd
F值	145.738	79.283	57.020
P值	< 0.001	< 0.001	< 0.001

表2 黄芪总黄酮对缺氧/复氧诱导的心肌细胞凋亡影响（ ± s, n = 3）

分组	凋亡率（%）	cleaved caspase-3	BCL2
对照	3.23±0.43	0.26±0.02	0.91±0.05
H/R	32.76±2.42^a	0.83±0.05^a	0.33±0.06^a
H/R+TFA-L	27.09±2.11^ab	0.71±0.06^ab	0.48±0.05^ab
H/R+TFA-M	19.21±1.59^abc	0.57±0.04^abc	0.65±0.05^abc
H/R+TFA-H	11.01±1.25^bcd	0.42±0.04^abcd	0.81±0.06^bcd
F值	145.738	79.283	57.020
P值	< 0.001	< 0.001	< 0.001

图1 黄芪总黄酮对缺氧/复氧诱导的心肌细胞凋亡影响注：a ~ e图分别为流式细胞术检测对照、H/R、H/R+TFA-L、H/R+TFA-M和H/R+TFA-H组心肌细胞凋亡；f图为Western blot检测cleaved caspase-3、BCL2蛋白表达

表3 黄芪总黄酮对缺氧/复氧诱导的心肌细胞氧化应激的影响（ ± s）

分组	实验次数	SOD （U/mg）	MDA （nmol/mg）	LDH （U/L）	ROS荧光强度（%）
对照	3	135.32±9.22	4.26±0.48	13.66±1.72	98.51±6.55
H/R	3	52.14±4.95^a	23.36±2.25^a	52.51±3.82^a	192.63±10.42^a
H/R+TFA-L	3	72.33±5.87^ab	18.17±1.67^ab	43.11±4.30^ab	166.11±9.88^ab
H/R+TFA-M	3	92.08±6.27^abc	14.08±1.22^abc	31.25±2.59^abc	141.52±8.94^abc
H/R+TFA-H	3	116.38±7.66^bcd	9.84±0.73^abcd	19.42±1.89^bcd	115.32±7.55^abcd
F值		68.708	80.604	84.136	55.808
P值		< 0.001	< 0.001	< 0.001	< 0.001

表3 黄芪总黄酮对缺氧/复氧诱导的心肌细胞氧化应激的影响（ ± s）

分组	实验次数	SOD （U/mg）	MDA （nmol/mg）	LDH （U/L）	ROS荧光强度（%）
对照	3	135.32±9.22	4.26±0.48	13.66±1.72	98.51±6.55
H/R	3	52.14±4.95^a	23.36±2.25^a	52.51±3.82^a	192.63±10.42^a
H/R+TFA-L	3	72.33±5.87^ab	18.17±1.67^ab	43.11±4.30^ab	166.11±9.88^ab
H/R+TFA-M	3	92.08±6.27^abc	14.08±1.22^abc	31.25±2.59^abc	141.52±8.94^abc
H/R+TFA-H	3	116.38±7.66^bcd	9.84±0.73^abcd	19.42±1.89^bcd	115.32±7.55^abcd
F值		68.708	80.604	84.136	55.808
P值		< 0.001	< 0.001	< 0.001	< 0.001

图2 黄芪总黄酮对缺氧/复氧诱导的心肌细胞中miR-190a-5p表达的影响注：与对照相比，^aP < 0.05；与H/R相比，^bP < 0.05；与H/R+TFA-L相比，^cP < 0.05；与H/R+TFA-M相比，^dP < 0.05；n = 9

表4 过表达miR-190a-5p对缺氧/复氧诱导的心肌细胞凋亡和氧化应激的影响（ ± s）

分组	实验次数	miR-190a-5p	凋亡率（%）	cleaved caspase-3	BCL2
H/R+miR-NC	3	0.34±0.05	33.07±2.52	0.82±0.07	0.34±0.04
H/R+miR-190a-5p	3	0.52±0.07	13.51±1.65	0.53±0.04	0.51±0.05
t值		3.624	11.248	6.230	4.599
P值		< 0.001	< 0.001	0.003	0.010
分组	实验次数	SOD（U/mg）	MDA（nmol/mg）	LDH（U/L）	ROS荧光强度（%）
H/R+miR-NC	3	51.27±4.98	24.08±3.24	50.68±4.83	180.11±12.45
H/R+miR-190a-5p	3	85.64±6.11	13.15±1.67	29.48±2.55	132.14±9.47
t值		7.552	5.194	6.723	5.312
P值		0.002	0.007	0.003	0.006

表4 过表达miR-190a-5p对缺氧/复氧诱导的心肌细胞凋亡和氧化应激的影响（ ± s）

分组	实验次数	miR-190a-5p	凋亡率（%）	cleaved caspase-3	BCL2
H/R+miR-NC	3	0.34±0.05	33.07±2.52	0.82±0.07	0.34±0.04
H/R+miR-190a-5p	3	0.52±0.07	13.51±1.65	0.53±0.04	0.51±0.05
t值		3.624	11.248	6.230	4.599
P值		< 0.001	< 0.001	0.003	0.010
分组	实验次数	SOD（U/mg）	MDA（nmol/mg）	LDH（U/L）	ROS荧光强度（%）
H/R+miR-NC	3	51.27±4.98	24.08±3.24	50.68±4.83	180.11±12.45
H/R+miR-190a-5p	3	85.64±6.11	13.15±1.67	29.48±2.55	132.14±9.47
t值		7.552	5.194	6.723	5.312
P值		0.002	0.007	0.003	0.006

图3 过表达miR-190a-5p对缺氧/复氧诱导的心肌细胞凋亡的影响注：a ~ b图为流式细胞术检测心肌细胞凋亡；c图为Western blot检测cleaved caspase-3、BCL2蛋白表达

表5 抑制miR-190a-5p可部分逆转黄芪总黄酮对缺氧/复氧诱导的心肌细胞凋亡和氧化应激的影响（ ± s）

分组	实验次数	miR-190a-5p	凋亡率（%）	cleaved caspase-3	BCL2
H/R+TFA-H+anti-miR-NC	3	0.74±0.06	9.70±0.82	0.40±0.05	0.76±0.07
H/R+TFA-H+anti-miR-190a-5p	3	0.38±0.03	13.84±1.30	0.72±0.06	0.56±0.03
t值		9.295	4.665	7.097	4.549
P值		0.001	0.010	0.002	0.010
分组	实验次数	SOD（U/mg）	MDA（nmol/mg）	LDH（U/L）	ROS荧光强度（%）
H/R+TFA-H+anti-miR-NC	3	114.52±10.21	9.53±0.82	18.42±1.56	112.34±10.31
H/R+TFA-H+anti-miR-190a-5p	3	75.20±6.47	17.36±1.55	30.54±2.73	149.57±11.23
t值		4.929	7.734	6.676	4.230
P值		0.008	0.002	0.003	0.013

表5 抑制miR-190a-5p可部分逆转黄芪总黄酮对缺氧/复氧诱导的心肌细胞凋亡和氧化应激的影响（ ± s）

分组	实验次数	miR-190a-5p	凋亡率（%）	cleaved caspase-3	BCL2
H/R+TFA-H+anti-miR-NC	3	0.74±0.06	9.70±0.82	0.40±0.05	0.76±0.07
H/R+TFA-H+anti-miR-190a-5p	3	0.38±0.03	13.84±1.30	0.72±0.06	0.56±0.03
t值		9.295	4.665	7.097	4.549
P值		0.001	0.010	0.002	0.010
分组	实验次数	SOD（U/mg）	MDA（nmol/mg）	LDH（U/L）	ROS荧光强度（%）
H/R+TFA-H+anti-miR-NC	3	114.52±10.21	9.53±0.82	18.42±1.56	112.34±10.31
H/R+TFA-H+anti-miR-190a-5p	3	75.20±6.47	17.36±1.55	30.54±2.73	149.57±11.23
t值		4.929	7.734	6.676	4.230
P值		0.008	0.002	0.003	0.013

图4 抑制miR-190a-5p可部分逆转黄芪总黄酮对缺氧/复氧诱导的心肌细胞凋亡的影响注：a~b图为流式细胞术检测心肌细胞凋亡；c图为Western blot检测cleaved caspase-3、BCL2蛋白表达

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Effects of total flavonids of astragalus on hypoxia/reoxygenation-induced cardiomyocyte injury by regulating miR-190a-5p and its molecular mechanism

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Effects of total flavonids of astragalus on hypoxia/reoxygenation-induced cardiomyocyte injury by regulating miR-190a-5p and its molecular mechanism