沉默<i>LncRNA MEG3</i>调控miR-424-5p/FoxO1对氧化型低密度脂蛋白诱导的动脉粥样硬化的保护机制

doi:10.3877/cma.j.issn.2095-1221.2022.06.003

目的

探究LncRNA MEG3在动脉粥样硬化（AS）发展中的作用及潜在机制。

方法

培养人脐静脉内皮细胞（HUVECs），采用氧化型低密度脂蛋白（ox-LDL）诱导建立内皮细胞损伤模型。ox-LDL干预HUVECs为ox-LDL组；分别用sh-NC、sh-MEG3、sh-MEG3和in- miR- 424-5p、sh-MEG3和oe-FoxO1转染后ox-LDL干预HUVECs设为ox-LDL+sh-NC组、ox-LDL+sh-MEG3组、ox-LDL+sh-MEG3+in-miR-424-5p组、ox-LDL+sh-MEG3+oe-FoxO1组；ox-LDL相同的溶剂处理HUVECs为对照。采用qRT-PCR法检测LncRNA MEG3、miR-424-5p和FoxO1 mRNA表达水平；采用CCK-8和EdU法检测细胞增殖；采用流式细胞术检测细胞凋亡；小管形成实验检测血管生成；Western blot法检测FoxO1蛋白、血管生成相关蛋白NOS3、VEGFA和CXCL12的水平；双荧光素酶实验检测LncRNA MEG3和miR-424-5p靶标关系；建立AS小鼠模型，油红O染色检测小鼠AS病变面积；伊文思蓝染色评估血管再内皮化程度。两组间比较采用t检验，多组间比较采用单因素方差分析，进一步两两比较采用SNK-q检验。

结果

与对照比较，ox-LDL组LncRNA MEG3表达（2.35±0.24比1.03±0.04）、FoxO1 mRNA和蛋白水平及细胞凋亡率上升（P均< 0.05）；miR-424-5p表达（0.37±0.05比1.03±0.08）、细胞活力、EdU阳性细胞数、小管管型分枝数、NOS3、VEGFA和CXCL12蛋白水平均下降（P均< 0.05）。与ox-LDL+sh-NC组比较，ox-LDL+sh-MEG3组LncRNA MEG3表达、FoxO1 mRNA和蛋白水平及细胞凋亡率下降；miR-424-5p表达、细胞活力、EdU阳性细胞数、小管管型分枝数及NOS3、VEGFA和CXCL12蛋白水平均上升（P均< 0.05）。抑制miR-424-5p或过表达FoxO1可部分逆转LncRNA MEG3沉默对ox-LDL刺激HUVECs的影响（P < 0.05）。LncRNA MEG3通过miR-424-5p靶向调控FoxO1表达（P < 0.05）。在体内，AS小鼠颈主动脉中LncRNA MEG3、FoxO1 mRNA和蛋白表达升高，而miR-424-5p、NOS3、VEGFA和CXCL12蛋白表达下调；同时AS病变面积增加，血管再内皮化受到抑制（P < 0.05）。沉默LncRNA MEG3后可改善上述AS小鼠的典型特征。

结论

沉默LncRNA MEG3通过调控miR-424-5p/FoxO1促进HUVECs增殖和血管生成，抑制细胞凋亡，减轻AS。

关键词: LncRNA MEG3, 动脉粥样硬化, 增殖, 凋亡, 血管生成

Objective

To explore the role and potential mechanism of LncRNA MEG3 in developing atherosclerosis (AS) .

Methods

Human umbilical vein endothelial cells (HUVECs) were cultured, and oxidized low-density lipoprotein (ox-LDL) was used to induce the endothelial cell injury model. The experiment was divided into a control group, ox-LDL group, ox-LDL+sh-NC group, ox-LDL+sh-MEG3 group, ox-LDL+sh-MEG3+in-miR-424-5p group, ox-LDL+sh-MEG3+oe-FoxO1 group. The expression levels of LncRNA MEG3, miR-424-5p and FoxO1 mRNA were detected by qRT-PCR; CCK-8 and EdU methods were used to detect cell proliferation; apoptosis was detected by flow cytometry; angiogenesis was detected by tubule formation assay; the levels of FoxO1 protein, angiogenesis related proteins NOS3, VEGFA and CXCL12 were determined by Western blot; dual luciferase assay detection of LncRNA MEG3 and miR-424-5p target relationship. The AS mouse model was established, and oil red O staining was used to detect the area of AS lesions in mice; Evans blue staining was used to evaluate the degree of vascular re-endothelialization. The t-test was used for comparison between two groups; the one-way analysis of variance was used for multiple groups, and the SNK-q test was used for further pairwise comparison.

Results

Compared with the control group, LncRNA MEG3 expression (2.35±0.24 vs 1.03±0.04) , FoxO1 mRNA and protein levels, and apoptosis rate were increased after ox-LDL group (P < 0.05) ; miR-424-5p expression (0.37±0.05 vs 1.03±0.08) , cell viability, number of EdU positive cells, the number of tubule branching, NOS3, VEGFA and CXCL12 protein levels were all decreased (P < 0.05) . Compared with the ox-LDL+sh-NC group, LncRNA MEG3 expression, FoxO1 mRNA and protein levels and cell apoptosis rate in ox-LDL+sh-MEG3 group decreased (P < 0.05) ; miR-424-5p expression (P < 0.05) , cell viability, number of EdU positive cells, number of tubule branching and protein levels of NOS3, VEGFA and CXCL12 were all increased (P < 0.05) . Inhibition of miR-424-5p or overexpression of FoxO1 partially reversed the effect of LncRNA MEG3 silencing on ox-LDL-stimulated HUVECs (P < 0.05) . LncRNA MEG3 regulated FoxO1 expression by targeting miR-424-5p (P < 0.05) . In vivo, LncRNA MEG3, FoxO1 mRNA and protein expression were elevated in the carotid aorta of AS mice, while miR-424-5p, NOS3, VEGFA and CXCL12 protein expression was down-regulated. The plaque area of AS was increased, and vascular reendothelialization was inhibited (P < 0.05) . Silencing of LncRNA MEG3 partly reversed the typical characteristics of AS mice.

Conclusion

Silencing LncRNA MEG3 attenuates AS by promoting the proliferation and angiogenesis of HUVECs and inhibiting cell apoptosis through regulating miR-424-5p/FoxO1.

Key words: LncRNA MEG3, Atherosclerosis, Proliferation, Apoptosis, Angiogenesis

表1 特异性引物序列表

基因	引物序列（5'-3'）	预期扩增产物长度（bp）
LncRNA MEG3	上游GTGGACAATGGTGTCCAGGC	215
	下游TTAACTCAGAGCGGGTCTCC
miR-424-5p	上游ACACTCCAGCTGGGCAGCAGCAATTCATGT	104
	下游TGGTGTCGTGGAGTCG
FoxO1	上游GAAGAAAGCATCTCTCCAGTC	187
	下游GATCATCCTGTTCGGTCATAAT
GAPDH	上游GTCAACGGATTTGGTCTGTATT	154
	下游AGTCTTCTGGGTGGCAGTGAT
U6	上游CTCGCTTCGGCAGCACA	98
	下游AACGCTTCACGAATTTGCGT

表1 特异性引物序列表

基因	引物序列（5'-3'）	预期扩增产物长度（bp）
LncRNA MEG3	上游GTGGACAATGGTGTCCAGGC	215
	下游TTAACTCAGAGCGGGTCTCC
miR-424-5p	上游ACACTCCAGCTGGGCAGCAGCAATTCATGT	104
	下游TGGTGTCGTGGAGTCG
FoxO1	上游GAAGAAAGCATCTCTCCAGTC	187
	下游GATCATCCTGTTCGGTCATAAT
GAPDH	上游GTCAACGGATTTGGTCTGTATT	154
	下游AGTCTTCTGGGTGGCAGTGAT
U6	上游CTCGCTTCGGCAGCACA	98
	下游AACGCTTCACGAATTTGCGT

图1 ox-LDL对HUVECs存活率的影响注：与ox-LDL 0 μg/mL比较，^aP < 0.05；与ox-LDL 25 μg/mL比较，^bP < 0.05；与ox-LDL 50 μg/mL比较，^cP < 0.05；与ox-LDL 75 μg/mL比较，^dP < 0.05 （n = 3）

表2 HUVECs中LncRNA MEG3、miR-424-5p和FoxO1表达检测（±s）

分组	实验次数	LncRNA MEG3	miR-424-5p	FoxO1 mRNA	FoxO1蛋白
对照	3	1.03±0.04	1.03±0.08	1.05±0.03	0.29±0.02
ox-LDL	3	2.35±0.24^a	0.37±0.05^a	2.19±0.20^a	0.75±0.07^a
ox-LDL+sh-NC	3	2.58±0.27^a	0.43±0.05^a	2.25±0.26^a	0.84±0.07^a
ox-LDL+sh-MEG3	3	1.62±0.14^abc	0.77±0.06^abc	1.32±0.12^bc	0.34±0.03^bc
ox-LDL+sh-MEG3+in-miR-424-5p	3	1.70±0.20^abc	0.55±0.04^abd	1.78±0.15^acd	0.49±0.04^abcd
ox-LDL+sh-MEG3+oe-FoxO1	3	1.59±0.14^abc	0.80±0.07^abc	1.84±0.16^ad	0.56±0.05^abcd
F值		27.081	53.193	23.72	56.688
P值		< 0.001	< 0.001	< 0.001	< 0.001

表2 HUVECs中LncRNA MEG3、miR-424-5p和FoxO1表达检测（±s）

分组	实验次数	LncRNA MEG3	miR-424-5p	FoxO1 mRNA	FoxO1蛋白
对照	3	1.03±0.04	1.03±0.08	1.05±0.03	0.29±0.02
ox-LDL	3	2.35±0.24^a	0.37±0.05^a	2.19±0.20^a	0.75±0.07^a
ox-LDL+sh-NC	3	2.58±0.27^a	0.43±0.05^a	2.25±0.26^a	0.84±0.07^a
ox-LDL+sh-MEG3	3	1.62±0.14^abc	0.77±0.06^abc	1.32±0.12^bc	0.34±0.03^bc
ox-LDL+sh-MEG3+in-miR-424-5p	3	1.70±0.20^abc	0.55±0.04^abd	1.78±0.15^acd	0.49±0.04^abcd
ox-LDL+sh-MEG3+oe-FoxO1	3	1.59±0.14^abc	0.80±0.07^abc	1.84±0.16^ad	0.56±0.05^abcd
F值		27.081	53.193	23.72	56.688
P值		< 0.001	< 0.001	< 0.001	< 0.001

图2 Western blot检测HUVECs中FoxO1蛋白水平注：1-6分别表示为对照、ox-LDL组、ox-LDL+sh-NC组、ox-LDL+sh-MEG3组、ox-LDL+sh-MEG3+in-miR-424-5p组和ox-LDL+sh-MEG3+oe-FoxO1组

表3 LncRNA MEG3对ox-LDL处理的HUVECs增殖、凋亡及血管生成的影响（ ± s，n = 3）

分组	细胞活力（%）	EdU阳性细胞数量（个）	细胞凋亡率（%）	小管管型分枝数（个）	NOS3	VEGFA	CXCL12
对照	100.00±0.00	34.87±3.05	8.15±0.89	582.63±39.25	0.85±0.05	0.95±0.08	0.80±0.06
ox-LDL	37.65±4.67^a	9.46±2.11^a	35.62±3.12^a	239.94±24.31^a	0.23±0.02^a	0.38±0.03^a	0.19±0.03^a
ox-LDL+sh-NC	40.12±5.20^a	10.32±1.99^a	37.54±4.05^a	243.15±25.06^a	0.24±0.03^a	0.41±0.05^a	0.21±0.02^a
ox-LDL+sh-MEG3	78.65±7.46^abc	25.25±2.68^abc	15.67±1.63^abc	456.30±31.28^abc	0.66±0.05^abc	0.78±0.06^abc	0.62±0.05^abc
ox-LDL+sh-MEG3+ in-miR-424-5p	55.38±5.12^abcd	13.40±1.77^ad	25.62±2.54^abcd	321.42±27.71^ad	0.39±0.04^abcd	0.56±0.04^abcd	0.36±0.03^abcd
ox-LDL+sh-MEG3+ oe-FoxO1	58.67±5.39^abcd	15.30±2.02^ad	28.65±2.13^acd	330.50±29.38^abcd	0.42±0.05^abcd	0.61±0.05^abcd	0.40±0.04^abcd
F值	64.160	57.772	58.067	59.832	103.76	49.320	103.564
P值	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001

表3 LncRNA MEG3对ox-LDL处理的HUVECs增殖、凋亡及血管生成的影响（ ± s，n = 3）

分组	细胞活力（%）	EdU阳性细胞数量（个）	细胞凋亡率（%）	小管管型分枝数（个）	NOS3	VEGFA	CXCL12
对照	100.00±0.00	34.87±3.05	8.15±0.89	582.63±39.25	0.85±0.05	0.95±0.08	0.80±0.06
ox-LDL	37.65±4.67^a	9.46±2.11^a	35.62±3.12^a	239.94±24.31^a	0.23±0.02^a	0.38±0.03^a	0.19±0.03^a
ox-LDL+sh-NC	40.12±5.20^a	10.32±1.99^a	37.54±4.05^a	243.15±25.06^a	0.24±0.03^a	0.41±0.05^a	0.21±0.02^a
ox-LDL+sh-MEG3	78.65±7.46^abc	25.25±2.68^abc	15.67±1.63^abc	456.30±31.28^abc	0.66±0.05^abc	0.78±0.06^abc	0.62±0.05^abc
ox-LDL+sh-MEG3+ in-miR-424-5p	55.38±5.12^abcd	13.40±1.77^ad	25.62±2.54^abcd	321.42±27.71^ad	0.39±0.04^abcd	0.56±0.04^abcd	0.36±0.03^abcd
ox-LDL+sh-MEG3+ oe-FoxO1	58.67±5.39^abcd	15.30±2.02^ad	28.65±2.13^acd	330.50±29.38^abcd	0.42±0.05^abcd	0.61±0.05^abcd	0.40±0.04^abcd
F值	64.160	57.772	58.067	59.832	103.76	49.320	103.564
P值	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001

图3 荧光显微镜下观察HUVECs增殖情况（EdU染色，×400）注：红色荧光为EdU阳性染色，蓝色荧光为细胞核染色，紫色为EdU阳性细胞；可见ox-LDL组和ox-LDL+sh-NC组中EdU阳性细胞数较对照组减少，ox-LDL+sh-MEG3组中EdU阳性细胞数较ox-LDL+sh-NC组增加，ox-LDL+sh-MEG3+in-miR-424-5p组和ox-LDL+sh-MEG3+oe-FoxO1组EdU阳性细胞数较ox-LDL+sh-MEG3组减少

图4 流式细胞术检测HUVECs凋亡注：a ~ f图分别为对照、ox-LDL、ox-LDL+sh-NC、ox-LDL+sh-MEG3、ox-LDL+sh-MEG3+in-miR-424-5p、ox-LDL+sh-MEG3+oe-FoxO1各组细胞凋亡情况

图5 光学显微镜下观察各组HUVECs小管形成结果（×200）注：a ~ f图分别为对照、ox-LDL、ox-LDL+sh-NC、ox-LDL+sh-MEG3、ox-LDL+sh-MEG3+in-miR-424-5p、ox-LDL+sh-MEG3+oe-FoxO1各组小管形成。ox-LDL组和ox-LDL+sh-NC组中小管管型分枝数较对照组减少，ox-LDL+sh-MEG3组中小管管型分枝数较ox-LDL+sh-NC组增加，ox-LDL+sh-MEG3+in-miR-424-5p组和ox-LDL+sh-MEG3+oe-FoxO1组小管管型分枝数较ox-LDL+sh-MEG3组减少

图6 Western blot检测HUVECs中NOS3、VEGFA和CXCL12蛋白表达注：1-6分别表示为对照组、ox-LDL组、ox-LDL+sh-NC组、ox-LDL+sh-MEG3组、ox-LDL+sh-MEG3+in-miR-424-5p组和ox-LDL+sh-MEG3+oe-FoxO1组

表4 双荧光素酶报告基因测定miR-424-5p与LncRNA MEG3或FoxO1 3' UTR之间的相互作用关系（ ± s）

分组	实验次数	MEG3-WT	MEG3-MUT	FoxO1-WT	FoxO1-MUT
miR-con	3	1.03±0.04	1.02±0.03	1.01±0.02	1.03±0.04
miR-424-5p	3	0.38±0.03	0.97±0.06	0.36±0.04	0.98±0.05
t值		22.517	1.291	25.174	1.353
P值		< 0.001	0.266	< 0.001	0.248

表4 双荧光素酶报告基因测定miR-424-5p与LncRNA MEG3或FoxO1 3' UTR之间的相互作用关系（ ± s）

分组	实验次数	MEG3-WT	MEG3-MUT	FoxO1-WT	FoxO1-MUT
miR-con	3	1.03±0.04	1.02±0.03	1.01±0.02	1.03±0.04
miR-424-5p	3	0.38±0.03	0.97±0.06	0.36±0.04	0.98±0.05
t值		22.517	1.291	25.174	1.353
P值		< 0.001	0.266	< 0.001	0.248

表5 LncRNA MEG3沉默对AS小鼠血管损伤恢复的影响（ ± s，n = 5）

分组	LncRNA EG3	miR-424-5p	FoxO1 mRNA	AS病变面积（%）	再内皮化程度（%）
对照	1.01±0.03	1.05±0.02	1.01±0.05	11.25±1.24	87.65±8.54
AS	2.15±0.22^a	0.40±0.03^a	1.98±0.17^a	42.39±4.08^a	24.37±2.51^a
AS+sh-NC	2.24±0.23^a	0.45±0.05^a	1.87±0.15^a	44.39±3.87^a	26.38±3.09^a
AS+sh-MEG3	1.57±0.15^abc	0.79±0.06^abc	1.45±0.13^abc	20.36±2.56^abc	52.39±5.45^abc
F值	50.835	252.320	55.167	135.035	147.242
P值	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001
分组	FoxO1蛋白	NOS3蛋白	VEGFA蛋白	CXCL12蛋白
对照	0.35±0.03	0.87±0.06	0.96±0.08	0.82±0.06
AS	0.89±0.08^a	0.32±0.04^a	0.42±0.04^a	0.26±0.03^a
AS+sh-NC	0.95±0.08^a	0.35±0.03^a	0.48±0.05^a	0.29±0.04^a
AS+sh-MEG3	0.50±0.04^abc	0.58±0.05^abc	0.60±0.05^abc	0.48±0.05^abc
F值	112.50	150.85	90.03	154.167
P值	< 0.001	< 0.001	< 0.001	< 0.001

表5 LncRNA MEG3沉默对AS小鼠血管损伤恢复的影响（ ± s，n = 5）

分组	LncRNA EG3	miR-424-5p	FoxO1 mRNA	AS病变面积（%）	再内皮化程度（%）
对照	1.01±0.03	1.05±0.02	1.01±0.05	11.25±1.24	87.65±8.54
AS	2.15±0.22^a	0.40±0.03^a	1.98±0.17^a	42.39±4.08^a	24.37±2.51^a
AS+sh-NC	2.24±0.23^a	0.45±0.05^a	1.87±0.15^a	44.39±3.87^a	26.38±3.09^a
AS+sh-MEG3	1.57±0.15^abc	0.79±0.06^abc	1.45±0.13^abc	20.36±2.56^abc	52.39±5.45^abc
F值	50.835	252.320	55.167	135.035	147.242
P值	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001
分组	FoxO1蛋白	NOS3蛋白	VEGFA蛋白	CXCL12蛋白
对照	0.35±0.03	0.87±0.06	0.96±0.08	0.82±0.06
AS	0.89±0.08^a	0.32±0.04^a	0.42±0.04^a	0.26±0.03^a
AS+sh-NC	0.95±0.08^a	0.35±0.03^a	0.48±0.05^a	0.29±0.04^a
AS+sh-MEG3	0.50±0.04^abc	0.58±0.05^abc	0.60±0.05^abc	0.48±0.05^abc
F值	112.50	150.85	90.03	154.167
P值	< 0.001	< 0.001	< 0.001	< 0.001

图7 Western blot检测小鼠中FoxO1、NOS3、VEGFA和CXCL12蛋白表达注：1 ~ 4分别表示为对照、AS组、AS+sh-NC组和AS+sh-MEG3组

图8 正常视野下观察各组小鼠AS斑块面积及血管再内皮化程度注：a图为小鼠AS斑块面积（油红O染色），可见AS组和AS+sh-NC组中AS病变面积较对照组增加，AS+sh-MEG3组中AS病变面积较AS组和AS+sh-NC组减少；b图为小鼠血管再内皮化程度（伊文思蓝染色），可见AS组和AS+sh-NC组中血管再内皮化程度较对照组降低，AS+sh-MEG3组中血管再内皮化程度较AS组和AS+sh-NC组升高

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Silencing LncRNA MEG3 regulates the protective mechanism of miR-424-5p/FoxO1 against oxidized low-density lipoprotein-induced atherosclerosis

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Silencing LncRNA MEG3 regulates the protective mechanism of miR-424-5p/FoxO1 against oxidized low-density lipoprotein-induced atherosclerosis