氟伐他汀对溶血磷脂酰胆碱诱导动脉平滑肌细胞增殖与凋亡相关基因表达的影响
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摘要
目的:观察氟伐他汀对溶血磷脂酰胆碱(LPC)诱导人脐动脉血管平滑肌细胞(HUASMC)增殖及凋亡相关基因的影响并探讨其机制,为他汀类药物的临床应用提供实验依据。
方法:原代培养人脐动脉平滑肌细胞待细胞生长融合后,用无血清DMEM培养液培养24h,使细胞同步化后分组进行实验。随机分成正常对照组、LPC组、氟伐他汀预孵育组,氟伐他汀预孵育组按浓度不同又分为10~(-5)mol·L~(-1)、10~(-6)mol·L~(-1)、10~(-7)mol·L~(-1),相同浓度(10~(-6)mol·L~(-1))氟伐他汀按时间不同又分为6h、12h、24h、48h、72h。用细胞计数和MTT比色法检测细胞增殖及细胞活力;比色法检测细胞和细胞培养液中NO的含量;Hoechst-33258染色法观察细胞凋亡情况;流式细胞仪测定细胞凋亡和细胞周期分布;免疫组织化学染色方法和RT-PCR测定血管平滑肌凋亡相关因子Survivin、Fas的表达。
结果:(1)溶血磷脂酰胆碱促进细胞增殖,使细胞数量和增殖指数增大,氟伐他汀能抑制5mg·L~(-1)溶血磷脂酰胆碱(LPC)对血管平滑肌细胞的增殖作用,使细胞NO释放量增加,细胞数量和增殖指数减少;(2)流式细胞仪观察LPC组血管平滑肌细胞处于DNA合成期和分裂期,S期的百分数高于对照组,氟伐他汀预孵育后使血管平滑肌细胞周期中的G0/G1期细胞比例增多,S期细胞比例减少,细胞凋亡率较对照组升高。(3)Hoechst-33258染色法发现:氟伐他汀诱导血管平滑肌细胞产生凋亡,随着作用时间延长和浓度增大细胞凋亡发生率增加,可见大量血管平滑肌细胞发生核碎裂和核边聚现象。(4)LPC增加Survivin的表达,细胞内可见大量棕黄色颗粒,氟伐他汀预孵育组6h时Survivin表达开始下降,24h下降最明显;Fas基因早期表达不明显,到48h、72h后明显表达
结论:氟伐他汀抑制LPC促HUASMC增殖作用,促进细胞发生凋亡,血管平滑肌细胞凋亡率升高,其促凋亡作用主要与上调FasmRNA表达,下调Survivin mRNA的表达有关。
Objective:The aim of this study was to clarify the effects of fluvastatin on the proliferation and expression of apoptosis related-gene on human umbilical artery vascular smooth muscle cells induced by lysophosphatidylcholine(LPC)and its mechanisms by using different experimental methods.This study can provide a evidence to statins in clinical application.
Methods:The HUASMC from Embryo Artery vein was primary cultured and identified withα-actin.The HUASMC were divided into 4 groups:Control group(no stimulation),LPC(5 mg·L~(-1))group,fluvastatin group:HUASMC were incubated with fluvastatin of different concentration(10~(-5)to 10~(-7)mol·L~(-1))for 1 hour before stimulated with lysophosphatidylcholine for 24 hours.Fluvastatin time groups:HUASMC were incubated with the same dose of fluvastatin for 1 hour before incubated with lysophosphatidylcholine for 6 h,12 h,24 h,48 h,72 h. The cell proliferation evaluated by cell counting and MTT assay,the cell cycle examined with Flow Cytometry,the apoptosis of HUASMC examined with dying Hoechst33258,the expression of Survivin and Fas detected in immunohistochemical methods,the mRNA expression of Survivin and Fas determined by reverse transcription polymerase chain reaction method(RT-PCR).
Results:(1)The proliferation and cell counting of vascular smooth muscle cells in LPC group was significantly increased compared with the control group,fluvastatin could inhibit the proliferation of LPC-induced HUASMC in a dose dependent manner.(2)Flow Cytometric DNA revealed that more vascular smooth muscle cells in LPC group got into the S or G2/M phase,and the apoptosis rate was makedly decreased as compared with the control.Fluvastatin could induce significantly enhancement at G0/G1 phase and arrenuation at S phase vascular smooth cell compared with LPC group.In a dose dependent manner the apoptosis rate increased makedly.(3)Hoechst-33258 revealed that apoptosis cells was increased with the time elapsing and the dose of fluvastatin increasing.(4)The LPC could significantly stimulate the mRNA expression of Survivin compared with the control group. Immunocytochemistry revealed that there were many brown particles in cells.Fluvastatin could inhibit the mRNA expression of Survivin in the early period,on the contrary,with the time elapsing,the mRNA expression of Fas become more and more strongly,at 72 h,the mRNA expression of Fas reach the peak.
Conclusion:Fluvastatin could inhibit proliferation on HUASMC induced by lysophosphatidylcholine(LPC).Fluvastatin could induce apoptosis associated with induction of Survivin,Fas and play a significant role down-regulation of Survivin and up-regulation of Fas on HUASMC.
方法:原代培养人脐动脉平滑肌细胞待细胞生长融合后,用无血清DMEM培养液培养24h,使细胞同步化后分组进行实验。随机分成正常对照组、LPC组、氟伐他汀预孵育组,氟伐他汀预孵育组按浓度不同又分为10~(-5)mol·L~(-1)、10~(-6)mol·L~(-1)、10~(-7)mol·L~(-1),相同浓度(10~(-6)mol·L~(-1))氟伐他汀按时间不同又分为6h、12h、24h、48h、72h。用细胞计数和MTT比色法检测细胞增殖及细胞活力;比色法检测细胞和细胞培养液中NO的含量;Hoechst-33258染色法观察细胞凋亡情况;流式细胞仪测定细胞凋亡和细胞周期分布;免疫组织化学染色方法和RT-PCR测定血管平滑肌凋亡相关因子Survivin、Fas的表达。
结果:(1)溶血磷脂酰胆碱促进细胞增殖,使细胞数量和增殖指数增大,氟伐他汀能抑制5mg·L~(-1)溶血磷脂酰胆碱(LPC)对血管平滑肌细胞的增殖作用,使细胞NO释放量增加,细胞数量和增殖指数减少;(2)流式细胞仪观察LPC组血管平滑肌细胞处于DNA合成期和分裂期,S期的百分数高于对照组,氟伐他汀预孵育后使血管平滑肌细胞周期中的G0/G1期细胞比例增多,S期细胞比例减少,细胞凋亡率较对照组升高。(3)Hoechst-33258染色法发现:氟伐他汀诱导血管平滑肌细胞产生凋亡,随着作用时间延长和浓度增大细胞凋亡发生率增加,可见大量血管平滑肌细胞发生核碎裂和核边聚现象。(4)LPC增加Survivin的表达,细胞内可见大量棕黄色颗粒,氟伐他汀预孵育组6h时Survivin表达开始下降,24h下降最明显;Fas基因早期表达不明显,到48h、72h后明显表达
结论:氟伐他汀抑制LPC促HUASMC增殖作用,促进细胞发生凋亡,血管平滑肌细胞凋亡率升高,其促凋亡作用主要与上调FasmRNA表达,下调Survivin mRNA的表达有关。
Objective:The aim of this study was to clarify the effects of fluvastatin on the proliferation and expression of apoptosis related-gene on human umbilical artery vascular smooth muscle cells induced by lysophosphatidylcholine(LPC)and its mechanisms by using different experimental methods.This study can provide a evidence to statins in clinical application.
Methods:The HUASMC from Embryo Artery vein was primary cultured and identified withα-actin.The HUASMC were divided into 4 groups:Control group(no stimulation),LPC(5 mg·L~(-1))group,fluvastatin group:HUASMC were incubated with fluvastatin of different concentration(10~(-5)to 10~(-7)mol·L~(-1))for 1 hour before stimulated with lysophosphatidylcholine for 24 hours.Fluvastatin time groups:HUASMC were incubated with the same dose of fluvastatin for 1 hour before incubated with lysophosphatidylcholine for 6 h,12 h,24 h,48 h,72 h. The cell proliferation evaluated by cell counting and MTT assay,the cell cycle examined with Flow Cytometry,the apoptosis of HUASMC examined with dying Hoechst33258,the expression of Survivin and Fas detected in immunohistochemical methods,the mRNA expression of Survivin and Fas determined by reverse transcription polymerase chain reaction method(RT-PCR).
Results:(1)The proliferation and cell counting of vascular smooth muscle cells in LPC group was significantly increased compared with the control group,fluvastatin could inhibit the proliferation of LPC-induced HUASMC in a dose dependent manner.(2)Flow Cytometric DNA revealed that more vascular smooth muscle cells in LPC group got into the S or G2/M phase,and the apoptosis rate was makedly decreased as compared with the control.Fluvastatin could induce significantly enhancement at G0/G1 phase and arrenuation at S phase vascular smooth cell compared with LPC group.In a dose dependent manner the apoptosis rate increased makedly.(3)Hoechst-33258 revealed that apoptosis cells was increased with the time elapsing and the dose of fluvastatin increasing.(4)The LPC could significantly stimulate the mRNA expression of Survivin compared with the control group. Immunocytochemistry revealed that there were many brown particles in cells.Fluvastatin could inhibit the mRNA expression of Survivin in the early period,on the contrary,with the time elapsing,the mRNA expression of Fas become more and more strongly,at 72 h,the mRNA expression of Fas reach the peak.
Conclusion:Fluvastatin could inhibit proliferation on HUASMC induced by lysophosphatidylcholine(LPC).Fluvastatin could induce apoptosis associated with induction of Survivin,Fas and play a significant role down-regulation of Survivin and up-regulation of Fas on HUASMC.
引文
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