【摘要】：目的:高同型半胱氨酸血癥(HHcy)是心血管疾病的獨(dú)立危險(xiǎn)因素(CVD)。我們實(shí)驗(yàn)團(tuán)隊(duì)先前證明,同型半胱氨酸(Hcy)抑制血管內(nèi)皮細(xì)胞(EC)細(xì)胞增殖、遷移和損傷后修復(fù),但Hcy誘導(dǎo)的EC損傷分子機(jī)制尚不清楚。在這項(xiàng)研究中,我們發(fā)現(xiàn)了一種新的F-BAR蛋白Carom,可介導(dǎo)的Hcy誘導(dǎo)的EC遷移和血管生成抑制。方法:1、實(shí)時(shí)熒光定量聚合酶鏈反應(yīng)(RT-PCR)和蛋白免疫印跡實(shí)驗(yàn)(WB)檢測(cè)人動(dòng)脈內(nèi)皮細(xì)胞(HAEC),24h 50μm DL-Hcy刺激后,Carom m RNA和蛋白在內(nèi)皮細(xì)胞的表達(dá)。2、高通量液相質(zhì)譜法檢測(cè)CBS KO小鼠同型半胱氨酸(Hcy)水平。WB檢測(cè)CBS KO小鼠主動(dòng)脈Carom的表達(dá),WB及流式細(xì)胞儀技術(shù)(FACS)檢測(cè)肺組織內(nèi)皮細(xì)胞中Carom的表達(dá)。3、高通量液相質(zhì)譜法檢測(cè)HAEC Hcy、S-腺蛋氨酸(SAM)和S-腺苷高半胱氨酸(SAH)水平,并計(jì)算SAM/SAH比例。用Actinnomyocin D及AZC處理內(nèi)皮細(xì)胞,RT-PCR檢測(cè)內(nèi)皮細(xì)胞Carom。4、Adv-Carom病毒或Carom Sh-RNA病毒轉(zhuǎn)染HAEC 72h,提取完整RNA,進(jìn)行Carom相關(guān)的microarray及cytokine array。5、Adv-Carom病毒或Carom Sh-RNA病毒轉(zhuǎn)染HAEC 72h,RT-PCR檢測(cè)Carom及CXCL10 m RNA的表達(dá)水平。6、Hcy干預(yù)24h,Adv-Carom或Carom Sh-RNA病毒轉(zhuǎn)染HAEC后72h,進(jìn)行細(xì)胞劃痕實(shí)驗(yàn),觀察Hcy和Carom對(duì)內(nèi)皮細(xì)胞遷移功能的影響。同時(shí)加入CXCL10中和抗體,細(xì)胞劃痕實(shí)驗(yàn)檢測(cè)內(nèi)皮細(xì)胞Carom和CXCLl0對(duì)細(xì)胞遷移功能的影響。7、Hcy干預(yù)細(xì)胞后,提取不同細(xì)胞成分的蛋白,WB鑒定Carom在細(xì)胞質(zhì),膜,細(xì)胞核及細(xì)胞骨架上表達(dá)變化。設(shè)計(jì)并合成Carom相關(guān)的NLS肽,內(nèi)皮細(xì)胞同時(shí)給予Hcy和NLS肽處理后,WB檢測(cè)Carom在染色質(zhì)結(jié)合細(xì)胞核(CB)中的表達(dá)。內(nèi)皮細(xì)胞Adv-Carom轉(zhuǎn)染和NLS肽處理后,RT-PCR檢測(cè)CXCLl0m RNA的表達(dá)。8、給予內(nèi)皮細(xì)胞Hcy或Carom相關(guān)病毒轉(zhuǎn)染后,體外進(jìn)行血管再生實(shí)驗(yàn),檢測(cè)Hcy和Carom對(duì)內(nèi)皮細(xì)胞血管再生的抑制作用。9、內(nèi)皮細(xì)胞給予Hcy或Carom相關(guān)病毒轉(zhuǎn)染后,分別給予兩種細(xì)胞內(nèi)吞抑制劑Mitmab和Chroquine,流式細(xì)胞儀檢測(cè)Hcy和Carom對(duì)人血管生長(zhǎng)因子受體2(VEGFR2)表達(dá)的影響。10、PIP array觀察GST-Carom融合蛋白對(duì)磷酸肌醇的結(jié)合能力。用生物素標(biāo)記膜蛋白,Hcy干預(yù)后觀察細(xì)胞膜蛋白內(nèi)吞的情況。11、內(nèi)皮細(xì)胞過(guò)表達(dá)Carom,免疫共沉淀聯(lián)合質(zhì)譜篩選,Carom可能的相互作用蛋白。結(jié)果:1、RT-PCR發(fā)現(xiàn)Hcy可誘導(dǎo)HAEC Carom m RNA的表達(dá),分別為對(duì)照組1.87倍(12h),2.72倍(24h)和2.45倍(48h)P0.05。同時(shí)DL-Hcy可誘導(dǎo)內(nèi)皮細(xì)胞Carom蛋白表達(dá)增加,并呈時(shí)間依賴性,48h Carom蛋白表達(dá)最高為對(duì)照組的2.2倍(P0.05)。2、發(fā)現(xiàn)12-16周Tg-h CBS Cbs-/-小鼠血漿Hcy水平為50-100μm,Tg-h CBS Cbs+/-和Tg-h CBS Cbs+/+小鼠血漿Hcy水平小于10μm。血漿Hcy水平高的Tg-h CBS Cbs-/-小鼠主動(dòng)脈及肺組織內(nèi)皮細(xì)胞Carom的表達(dá)高于對(duì)照組小鼠,是對(duì)照組小鼠的1.4倍和1.6倍(P0.05)。3、Hcy干預(yù)可增加內(nèi)皮細(xì)胞SAH水平約為對(duì)照組的1.8倍(P0.05),降低了內(nèi)皮細(xì)胞SAM/SAH的比例由原來(lái)2.2降為0.5左右(P0.05),導(dǎo)致內(nèi)皮細(xì)胞的低甲基化水平。Actinomyosin D可阻斷Hcy誘導(dǎo)內(nèi)皮細(xì)胞Carom m RNA的表達(dá)。不同濃度甲基化抑制劑AZC干預(yù)內(nèi)皮細(xì)胞后,Carom蛋白的表達(dá)增加分別為對(duì)照組的1.9和2.2倍(P0.05)。4、Carom microarray篩選發(fā)現(xiàn),與Adv-CT轉(zhuǎn)染組相比,Adv-Carom轉(zhuǎn)染組可使459個(gè)基因表達(dá)上調(diào)和460個(gè)基因表達(dá)下降(P0.05,FC1.2),Sh-RNA Carom可使653個(gè)基因表達(dá)下降,537個(gè)基金表達(dá)升高(P0.05,FC1.2)。其中有42個(gè)基因同時(shí)受Adv-Carom升高和sh-RNA Carom下降的調(diào)節(jié)。13個(gè)基因同時(shí)受Adv-Carom下降和sh-RANA Carom升高的調(diào)節(jié)。其中受Carom病毒轉(zhuǎn)染變化最大的基因是CXCL10。5、DL-Hcy 50μm分別干預(yù)HAEC 12h、24h、48h小時(shí),RT-PCR發(fā)現(xiàn)同型半胱氨酸增加內(nèi)皮細(xì)胞Carom m RNA表達(dá)的同時(shí),也增加CXCL10 m RNA的表達(dá),并且在24h表達(dá)最高,升高為對(duì)照組22.1倍(P0.05)。用內(nèi)皮細(xì)胞過(guò)表達(dá)Carom后發(fā)現(xiàn),Adv-Carom不僅能升高Carom m RNA的表達(dá),同時(shí)CXCL10 m RNA也升高為對(duì)照組的27.5倍(P0.05)。Carom Sh-RNA轉(zhuǎn)染后,可抑制同型半胱氨酸誘導(dǎo)Carom的表達(dá)0.32倍(P0.05),同時(shí)抑制Hcy誘導(dǎo)CXCL10 m RNA的表達(dá)1.1倍(P0.05)。6、細(xì)胞劃痕實(shí)驗(yàn)發(fā)現(xiàn),Hcy刺激或Adv Carom病毒轉(zhuǎn)染可抑制內(nèi)皮細(xì)胞的遷移,Carom sh-RNA可改善Hcy對(duì)內(nèi)皮細(xì)胞遷移的抑制作用(P0.05),CXCLl0中和抗體(a-CXCL10)可減輕Carom對(duì)內(nèi)皮細(xì)胞遷移的抑制作用(P0.05)。7、WB結(jié)果發(fā)現(xiàn)Carom除了在細(xì)胞膜(ME)表達(dá)最多外,Carom還可以在細(xì)胞質(zhì)(CE),可溶性細(xì)胞核(NE),染色質(zhì)結(jié)合細(xì)胞核(CB)和細(xì)胞骨架(PE)中表達(dá)。同型半胱氨酸干預(yù)內(nèi)皮細(xì)胞(HAEC)24h,Carom蛋白主要在CB和PE中表達(dá)增加,分別為對(duì)照組2.2倍和1.75倍(P0.05)。Carom NLS肽可減少同型半胱氨酸誘導(dǎo)Carom在染色質(zhì)結(jié)合細(xì)胞核(CB)中的表達(dá),同時(shí)可抑制Carom誘導(dǎo)的CXCLl0 m RNA的表達(dá),提示Carom調(diào)節(jié)CXCLl0的表達(dá)可能與細(xì)胞核內(nèi)Carom的表達(dá)和Carom的入核運(yùn)動(dòng)相關(guān)。8、內(nèi)皮細(xì)胞小管形成實(shí)驗(yàn)發(fā)現(xiàn),內(nèi)皮細(xì)胞降低Carom表達(dá)后,可改善同型半胱氨酸對(duì)內(nèi)皮細(xì)胞血管生成的抑制作用,由原來(lái)的35%升高為80%(P0.05),新生血管數(shù)量由原來(lái)的20上升至42(P0.05);內(nèi)皮細(xì)胞過(guò)表達(dá)Carom可明顯抑制內(nèi)皮細(xì)胞血管再生過(guò)程(P0.05)。Carom對(duì)內(nèi)皮細(xì)胞的增值作用無(wú)影響。9、流式細(xì)胞儀檢測(cè)發(fā)現(xiàn),與Adv-CT相比,過(guò)表達(dá)Carom組內(nèi)皮細(xì)胞膜VEGFR2明顯減少為28.6%(P0.05),同型半胱氨酸也可抑制VEGFR2在內(nèi)皮細(xì)胞的表達(dá)為41%(P0.05),同時(shí)給予Sh-RNA Carom病毒轉(zhuǎn)染后VEGFR2的表達(dá)升高為49%(P0.05,無(wú)統(tǒng)計(jì)學(xué)意義)。內(nèi)吞抑制劑Mitmab可改善同型半胱氨酸和Adv-Carom對(duì)內(nèi)皮細(xì)胞膜VEGFR2表達(dá)的抑制,分別由原來(lái)39%升高至58%,39%升高至51%(P0.05),Chroquine對(duì)VEGFR2表達(dá)無(wú)影響。10、PIP array表明GST-Carom融合蛋白易與各種磷酸肌醇結(jié)合,對(duì)Ptdlns(3)P及Ptdlns(3,5)P親和力最大。細(xì)胞膜蛋白生物素標(biāo)記細(xì)胞內(nèi)吞實(shí)驗(yàn)表明,Hcy可誘導(dǎo)內(nèi)皮細(xì)胞Carom及VEGFR2的內(nèi)吞作用。11、免疫共沉淀蛋白印跡實(shí)驗(yàn)(Co-IP)發(fā)現(xiàn)在Hcy刺激下,Carom不能與VEGFR2,CASK和MAGI1連接發(fā)生相互作用。過(guò)表達(dá)Carom免疫共沉淀聯(lián)合蛋白質(zhì)譜分析發(fā)現(xiàn),Carom可能在內(nèi)皮細(xì)胞有13個(gè)相互作用蛋白,其中TRIM21可能通過(guò)與Carom連接,參與和介導(dǎo)Carom在內(nèi)皮細(xì)胞的內(nèi)吞。結(jié)論:1、Carom可在Hcy誘導(dǎo)的內(nèi)皮細(xì)胞和高Hcy血癥的小鼠肺內(nèi)皮細(xì)胞和主動(dòng)脈中高表達(dá),其機(jī)制可能與內(nèi)皮細(xì)胞低甲基化水平相關(guān)。2、過(guò)表達(dá)Carom可增加CXCLl0 m RNA的表達(dá),Carom可能通過(guò)CXCLl0介導(dǎo)Hcy對(duì)內(nèi)皮細(xì)胞遷移功能的抑制,其機(jī)制可能與Carom NLS介導(dǎo)的染色質(zhì)結(jié)合細(xì)胞核(CB)Carom的表達(dá)增加及Carom的入核運(yùn)動(dòng)相關(guān)。3、Carom可介導(dǎo)Hcy對(duì)內(nèi)皮細(xì)胞血管生成的抑制,抑制內(nèi)皮細(xì)胞膜VEGFR2的表達(dá),其機(jī)制可能與Carom介導(dǎo)的細(xì)胞內(nèi)吞作用相關(guān)。
[Abstract]:AIM: Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease (CVD). Our team has previously demonstrated that homocysteine inhibits the proliferation, migration and repair of vascular endothelial cells (EC) cells, but the molecular mechanism of Hcy-induced EC injury remains unclear. F-BAR protein Carom can mediate Hcy-induced EC migration and angiogenesis inhibition. Methods: 1. Real-time fluorescence quantitative polymerase chain reaction (RT-PCR) and protein immunoblotting assay (WB) were used to detect the expression of Carom m RNA and protein in human arterial endothelial cells (HAEC), 24 h 50 micron DL-Hcy stimulation, and high-throughput liquid chromatography-mass spectrometry was used to detect CBS KO. The levels of homocysteine (Hcy) in mice were measured by WB. The expression of Carom in the aorta of CBS KO mice was detected by WB. The expression of Carom in lung endothelial cells was detected by WB and FACS. The levels of HAEC Hcy, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) were detected by high-throughput liquid chromatography-mass spectrometry. The ratio of SAM to SAH was calculated by Actinnomyocin D and FACS. Endothelial cells were treated with AZC. Carom 4, Adv-Carom virus or Carom Sh-RNA virus were transfected into HAEC by RT-PCR for 72 hours. Complete RNA was extracted and transfected with Carom-related microarray and cytokine array. 72 hours after transfection of HAEC with rom-Sh-RNA virus, the effects of Hcy and Carom on the migration of endothelial cells were observed. At the same time, CXCL-10 neutralizing antibody was added. The effects of Carom and CXCLl-0 on the migration of endothelial cells were detected by cell scratch test. 7. After Hcy interfered with cells, the proteins of different cell components were extracted and the Carom was identified by WB. Carom-related NLS peptides were designed and synthesized. After endothelial cells were treated with Hcy and NLS peptides, the expression of Carom in chromatin-binding nucleus (CB) was detected by WB. After endothelial cells were transfected with Adv-Carom and NLS peptides, the expression of CXCLl0m RNA was detected by RT-PCR. Hcy or Caro peptides were given to endothelial cells. Vascular regeneration test was carried out in vitro after transfection of m-associated virus to detect the inhibitory effect of Hcy and Carom on vascular regeneration of endothelial cells. 9. After transfection of Hcy or Carom-related virus, endothelial cells were given two kinds of endocytosis inhibitors Mitmab and Chroquine respectively. The expression of human vascular growth factor receptor 2 (VEGFR2) was detected by flow cytometry. PIP array was used to observe the binding ability of GST-Carom fusion protein to inositol phosphate.Biotin-labeled membrane protein was used to observe the endocytosis of membrane protein after Hcy intervention.11.Overexpression of Carom in endothelial cells was observed.Immunocoprecipitation combined with mass spectrometry was used to screen the possible interaction protein of Carom.Results:1.RT-PCR showed that Hcy could induce HAEC Caro. The expression of M RNA was 1.87 times (12h), 2.72 times (24h) and 2.45 times (48h) of the control group, respectively, P 0.05. DL-Hcy could induce the expression of Carom protein in endothelial cells in a time-dependent manner. The highest expression of Carom protein was 2.2 times (P 0.05). It was found that the plasma Hcy level of Tg-h CBS Cbs-/-mice at 12-16 weeks was 50-100um, Tg-h CBS Cbs+/-and Tg-h CBS Cbs-/-2, respectively. The levels of plasma Hcy in Tg-h CBS Cbs+/+ mice were less than 10 microns. The expression of Carom in endothelial cells of aorta and lung tissue of Tg-h CBS Cbs-/- mice with high plasma Hcy level was 1.4 and 1.6 times higher than that of control mice (P 0.05). Hcy intervention could increase the level of SAH in endothelial cells by 1.8 times (P 0.05), and decrease the level of SAH in endothelial cells. Actinomyosin D blocked Hcy-induced expression of Carom m RNA in endothelial cells. The expression of Carom protein increased by 1.9 and 2.2 times (P 0.05). Carom microarray sieve and AZC at different concentrations increased the expression of Carom protein in endothelial cells, respectively. Compared with the Adv-CT transfection group, the Adv-Carom transfection group could up-regulate the expression of 459 genes and down-regulate the expression of 460 genes (P 0.05, FC1.2), Sh-RNA Carom could down-regulate the expression of 653 genes and up-regulate the expression of 537 funds (P 0.05, FC1.2). Among them, CXCL10.5 was the most variable gene transfected by Carom virus, and DL-Hcy 50 micron interfered with HAEC 12 h, 24 h and 48 h respectively. RT-PCR showed that homocysteine increased the expression of Carom RNA and CXCL10 m RNA in endothelial cells, and the expression was the highest at 24 h, up to 0. Overexpression of Carom in endothelial cells showed that Adv-Carom not only increased the expression of Carom m RNA, but also increased the expression of CXCL10 m RNA by 27.5 times (P 0.05). Carom Sh-RNA transfection inhibited homocysteine-induced expression of Carom by 0.32 times (P 0.05) and inhibited Hcy-induced expression of CXCL10 m RNA by 1.1 times (P 0.0). 5) 6. Cell scratch test showed that Hcy stimulation or Adv Carom virus transfection could inhibit endothelial cell migration, Carom sh-RNA could improve the inhibition of Hcy on endothelial cell migration (P 0.05), CXCLl0 neutralizing antibody (a-CXCL10) could reduce the inhibition of Carom on endothelial cell migration (P 0.05). 7. WB results showed that Carom was expressed in the cell membrane (ME) except for Hcy. At most, Carom could also be expressed in cytoplasm (CE), soluble nucleus (NE), chromatin-binding nucleus (CB) and cytoskeleton (PE). Homocysteine interfered with endothelial cells (HAEC) for 24 hours, and the expression of Carom protein increased mainly in CB and PE, which were 2.2 and 1.75 times higher than that in control group (P 0.05). Carom NLS peptide decreased the induction of Ca by homocysteine. The expression of ROM in chromatin-binding cell nucleus (CB) and the expression of CXCLl0 m RNA induced by Carom were inhibited, suggesting that the expression of CXCLl0 regulated by Carom may be related to the expression of Carom in the nucleus and the movement of Carom into the nucleus. 8. Tubular formation experiment of endothelial cells showed that endothelial cells could improve homocysteine pairs by reducing the expression of Carom. The inhibition of endothelial cell angiogenesis increased from 35% to 80% (P 0.05), and the number of neovascularization increased from 20% to 42 (P 0.05). Overexpression of Carom in endothelial cells significantly inhibited the process of endothelial cell angiogenesis (P 0.05). Carom had no effect on endothelial cell proliferation. The expression of vascular endothelial growth factor R2 was significantly decreased by 28.6% (P Inhibition of the expression of VEGF R2 on the cell membrane increased from 39% to 58% and 39% to 51% (P 0.05), respectively. Chroquine had no effect on the expression of VEGF R2. 10. PIP array showed that GST-Carom fusion protein was easy to bind to various inositol phosphate and had the highest affinity for Ptdlns (3) P and Ptdlns (3,5) P. Carom could not interact with the binding of VEGFR2, CASK and MAGI1 under the stimulation of Hcy. Overexpression of Carom immunoprecipitation combined with protein profiling revealed that Carom may have 13 interacting proteins in endothelial cells, including TRIM21. Conclusion: 1. Carom can be highly expressed in Hcy-induced endothelial cells and in the pulmonary endothelial cells and aortas of mice with hypercythemia. The mechanism may be related to the hypomethylation level of endothelial cells. 2. Overexpression of Carom can increase the expression of CXCLl0 m RNA. Carom may increase the expression of CXCLl0 m RNA through CXCLl0. The mechanism of Hcy-mediated inhibition of endothelial cell migration may be related to the increased expression of Carom in the chromatin-binding nucleus (CB) mediated by Carom NLS and the movement of Carom into the nucleus. 3. Carom can mediate the inhibition of Hcy on endothelial cell angiogenesis and inhibit the expression of VEGF R2 in endothelial cell membrane. The mechanism may be Carom-mediated endocytosis. Function related.
【學(xué)位授予單位】：南昌大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R54

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8 苑t，

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