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通讯作者:

徐索文(1984-),男,安徽黄山人,博士生导师,主要从事心血管与代谢病的转化研究。E-mail:sxu1984@ustc.edu.cn

中图分类号:R543,R-1,R363.2+1

文献标识码:A

文章编号:2096-8965(2021)04-0067-08

DOI:10.12287/j.issn.2096-8965.20210409

参考文献 1
JARRAY R,ALLAIN B,BORRIELLO L,et al.Depletion of the novel protein PHACTR-1 from human endothelial cells abolishes tube formation and induces cell death receptor apoptosis[J].Biochimie,2011,93(10):1668-1675.
参考文献 2
ALLAIN B,JARRAY R,BORRIELLO L,et al.Neuropilin-1 regulates a new vegf-induced gene,phactr-1 which controls tubulogenesis and modulates lamellipodial dynamics in human endothelial cells[J].Cell Signal,2012,24(1):214-223.
参考文献 3
HAMADA N,OGAYA S,NAKASHIMA M,et al.De novo PHACTR1 mutations in west syndrome and their pathophysiological effects[J].Brain,2018,141(11):3098-3114.
参考文献 4
MARAKHONOV A V,PŘECHOVÁ M,KONOVALOV FA,et al.Mutation in PHACTR1 associated with multifocal epilepsy with infantile spasms and hypsarrhythmia[J].Clin Genet,2021,99(5):673-683.
参考文献 5
UITTERLINDEN A G.An introduction to genome-wide association studies:gwas for dummies[J].Semin Reprod Med,2016,34(4):196-204.
参考文献 6
GUPTA R M,HADAYA J,TREHAN A,et al.A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression[J].Cell,2017,170(3):522-533.
参考文献 7
LI T,DING L J,WANG Y G,et al.Genetic deficiency of phactr1 promotes atherosclerosis development via facilitating m1 macrophage polarization and foam cell formation[J].Clin Sci(Lond),2020,134(17):2353-2368.
参考文献 8
KASIKARA C,SCHILPEROORT M,GERLACH B,et al.Deficiency of macrophage phactr1 impairs efferocytosis and promotes atherosclerotic plaque necrosis[J].J Clin Invest,2021,131(8):e145275.
参考文献 9
JARRAY R,PAVONI S,BORRIELLO L,et al.Disruption of phactr-1 pathway triggers pro-inflammatory and pro-atherogenic factors:new insights in atherosclerosis development[J].Biochimie,2015,118:151-161.
参考文献 10
ZHANG Z H,JIANG F L,ZENG L X,et al.PHACTR1 regulates oxidative stress and inflammation to coronary artery endothelial cells via interaction with NF-κB/p65[J].Atherosclerosis,2018,278:180-189.
参考文献 11
JING Y,ZHANG L,XU Z M,et al.Phosphatase actin regulator-1(PHACTR-1)knockdown suppresses cell proliferation and migration and promotes cell apoptosis in the bend.3 mouse brain capillary endothelial cell line[J].Med Sci Monit,2019,25:1291-1300.
参考文献 12
AHERRAHROU R,AHERRAHROU Z,SCHUNKERT H,et al.Coronary artery disease associated gene phactr1 modulates severity of vascular calcification in vitro[J].Biochem Biophys Res Commun,2017,491(2):396-402.
参考文献 13
WIEZLAK M,DIRING J,ABELLA J,et al.G-actin regulates the shuttling and pp1 binding of the rpel protein PHACTR1 to control actomyosin assembly[J].J Cell Sci,2012,125(Pt23):5860-5872.
参考文献 14
FEDORYSHCHAK R O,PŘECHOVÁ M,BUTLER A M,et al.Molecular basis for substrate specificity of the PHACTR1/pp1 phosphatase holoenzyme[J].Elife,2020,9:e61509.
参考文献 15
MOUILLERON S,WIEZLAK M,O'REILLY N,et al.Structures of the PHACTR1 rpel domain and rpel motif complexes with g-actin reveal the molecular basis for actin binding cooperativity[J].Structure,2012,20(11):1960-1970.
参考文献 16
FILS-AIMÉ N,DAI M,GUO J,et al.Microrna-584 and the protein phosphatase and actin regulator 1(PHACTR1),a new signaling route through which transforming growth factor-β mediates the migration and actin dynamics of breast cancer cells[J].J Biol Chem,2013,288(17):11807-11823.
参考文献 17
ZHAO Y T,ZHU R X,XIAO T L,et al.Genetic variants in migraine:a field synopsis and systematic re-analysis of meta-analyses[J].J Headache Pain,2020,21(1):13.
参考文献 18
FREILINGER T,ANTTILA V,DE VRIES B,et al.Genome-wide association analysis identifies susceptibility loci for migraine without aura[J].Nat Genet,2012,44(7):777-782.
参考文献 19
WINSVOLD B S,BETTELLA F,WITOELAR A,et al.Shared genetic risk between migraine and coronary artery disease:a genome-wide analysis of common variants[J].PLoS One,2017,12(9):e0185663.
参考文献 20
GREEN I E,RAHMAN S A,OWENS D L,et al.Cervical artery dissection in patients of african ancestry [J].Cerebrovasc Dis,2018,46(5-6):218-222.
参考文献 21
ABE A,NITO C,SAKAMOTO Y,et al.Spontaneous bilateral cervical internal carotid and vertebral artery dissection in a japanese patient without collagen vascular disease with special reference to single-nucleotide polymorphisms[J].J Stroke Cerebrovasc Dis,2016,25(8):e114-117.
参考文献 22
ADLAM D,OLSON T M,COMBARET N,et al.Association of the PHACTR1/EDN1 genetic locus with spontaneous coronary artery dissection[J].J Am Coll Cardiol,2019,73(1):58-66.
参考文献 23
TURLEY T N,O'BYRNE M M,KOSEL M L,et al.Identification of susceptibility loci for spontaneous coronary artery dissection[J].JAMA Cardiol,2020,5(8):929-938.
参考文献 24
SAW J,YANG M L,TRINDER M,et al.Chromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction[J].Nat Commun,2020,11(1):4432.
参考文献 25
COMBARET N,GERBAUD E,DÉRIMAY F,et al.National french registry of spontaneous coronary artery dissections:prevalence of fibromuscular dysplasia and genetic analyses[J].EuroIntervention,2021,17(6):508-515.
参考文献 26
NARULA N,KADIAN-DODOV D,OLIN J W.Fibromuscular dysplasia:contemporary concepts and future directions[J].Prog Cardiovasc Dis,2018,60(6):580-585.
参考文献 27
TOUZÉ E,SOUTHERLANDAM,BOULANGER M,et al.Fibromuscular dysplasia and its neurologic manifest-ations:a systematic review[J].JAMA Neurol,2019,76(2):217-226.
参考文献 28
WARCHOL-CELINSKA E,BERRANDOU T,PREJBISZ A,et al.Genetic study of phactr1 and fibromuscular dysplasia,meta-analysis and effects on clinical features of patients:the arcadia-pol study[J].Hypertension,2020,76(1):e4-e7.
参考文献 29
KIANDO S R,TUCKER N R,CASTRO-VEGA L J,et al.Phactr1 is a genetic susceptibility locus for fibromuscular dysplasia supporting its complex genetic pattern of inheritance[J].PLoS Genet,2016,12(10):e1006367.
参考文献 30
GEORGES A,YANG M L,BERRANDOU T E,et al.Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases[J].Nat Commun,2021,12(1):6031.
参考文献 31
LIP S,PADMANABHAN S.Genomics of blood pressure and hypertension:extending the mosaic theory toward stratification[J].Can J Cardiol,2020,36(5):694-705.
参考文献 32
FUJIMAKI T,OGURI M,HORIBE H,et al.Association of a transcription factor 21 gene polymorphism with hypertension[J].Biomed Rep,2015,3(1):118-122.
参考文献 33
LI Z J,HU X,WAN J P,et al.The alleles of agt and hif1a gene affect the risk of hypertension in plateau residents[J].Exp Biol Med(Maywood),2021,246:1-9.
参考文献 34
CHEN L,QIAN H,LUO Z,et al.Phactr1 gene polymorphism with the risk of coronary artery disease in chinese han population[J].Postgrad Med J,2019,95(1120):67-71.
参考文献 35
SUN X,SUN J,ZHAO D,et al.Phosphatase and actin regulator 1 rs9349379 polymorphism is associated with an elevated susceptibility to coronary artery disease:a meta-analysis[J].J Biol Regul Homeost Agents,2019,33(3):925-928.
参考文献 36
O'DONNELL C J,KAVOUSI M,SMITH A V,et al.Genome-wide association study for coronary artery calcification with follow-up in myocardial infarction[J].Circulation,2011,124(25):2855-2864.
参考文献 37
HAGER J,KAMATANI Y,CAZIER J B,et al.Genome-wide association study in a lebanese cohort confirms phactr1 as a major determinant of coronary artery stenosis [J].PLoS One,2012,7(6):e38663.
参考文献 38
PÉREZ-HERNÁNDEZ N,VARGAS-ALARCÓN G,POSADAS-SÁNCHEZ R,et al.Phactr1 gene polymorphism is associated with increased risk of developing premature coronary artery disease in mexican population[J].Int J Environ Res Public Health,2016,13(8):803.
参考文献 39
LU X,WANG L,CHEN S,et al.Genome-wide association study in han chinese identifies four new susceptibility loci for coronary artery disease[J].Nat Genet,2012,44(8):890-894.
参考文献 40
ZHAO Q,WEI H,LIU D,et al.Phactr1 and slc22a3 gene polymorphisms are associated with reduced coronary artery disease risk in the male Chinese han population[J].Oncotarget,2017,8(1):658-663.
参考文献 41
RESCHEN M E,LIN D,CHALISEY A,et al.Genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene phactr1[J].Atherosclerosis,2016,250:95-105.
参考文献 42
BEAUDOIN M,GUPTA R M,WON H H,et al.Myocardial infarction-associated snp at 6p24 interferes with mef2 binding and associates with phactr1 expression levels in human coronary arteries[J].Arterioscler Thromb Vasc Biol,2015,35(6):1472-1479.
参考文献 43
CODINA-FAUTEUX V A,BEAUDOIN M,LALONDE S,et al.Phactr1 splicing isoforms and eqtls in atherosclerosis-relevant human cells[J].BMC Med Genet,2018,19(1):97.
参考文献 44
ALLEN P B,GREENFIELD A T,SVENNINGSSON P,et al.Phactrs 1-4:a family of protein phosphatase 1 and actin regulatory proteins[J].Proc Natl Acad Sci U S A,2004,101(18):7187-7192.
参考文献 45
FLEMING M R,BROWN M R,KRONENGOLD J,et al.Stimulation of slack k(+)channels alters mass at the plasma membrane by triggering dissociation of a phosphatase-regulatory complex[J].Cell Rep,2016,16(9):2281-2288.
目录contents

    摘要

    最近的全基因组关联研究发现并确认Phactr1是一个与多种血管疾病相关的风险基因。但是,Phactr1如何调控血管疾病的发生发展尚不明确。近年来的研究表明:Phactr1编码了一种能与肌动蛋白和蛋白磷酸酶1结合的蛋白,可以调节内皮细胞的增殖、凋亡、迁移和管形成,影响巨噬细胞的极化,以及血管平滑肌细胞的钙化。本文围绕Phactr1与多血管疾病的相关性及Phactr1调控动脉粥样硬化的分子机制,阐述Phactr1在多血管疾病进程中的作用和治疗潜力。

    Abstract

    Recent genome-wide association studies have identified Phactr1 as a risk gene associated with polyvascular diseases. However, it remains elusive how Phactr1 is involved in the pathogenesis of vascular diseases. More recently, mounting evidence has suggested that PHACTR1 as an actin and protein phosphatase 1 binding protein, regulates endothelial proliferation, apoptosis, migration and tube formation, affects polarization in macrophages, and aggravates calcification in vascular smooth muscle cells. This paper focuses on the correlation between Phactr1 and polyvascular disease, and the molecular mechanism of Phactr1 in regulating atherosclerosis. We thus provided an overview of the role and therapeutic potential of Phactr1 in the progression of polyvascular disease.

  • 前言

  • Phosphatase and actin regulator1 (Phactr1) 编码的蛋白质是磷酸酶和肌动蛋白调节子1,它在肾小管形成和内皮细胞存活中起作用[1, 2]。该基因的选择性剪接导致多个转录本的变异。此外,与 Phactr1 相关的疾病包括发育性和癫痫性脑病和West综合征[3, 4]。结构上,PHACTR1是一种肌动蛋白和蛋白质磷酸酶1 (Protein Serine/Threonine Phos⁃ phatase-1, PP1) 结合蛋白,据报道它在大脑中高度表达,并控制PP1活性和F-actin重塑[1]。随着十多年前全基因组关联研究(Genome-Wide Associa⁃tion Studies,GWAS) 的引入,在人类遗传多样性的研究和适用于高通量、大规模数据集成的新型DNA分析技术的开发推动下,有关致病基因、等位基因的鉴定发生了重大的变化[5]。目前,GWAS的基因挖掘覆盖了许多临床和基础研究领域。近十年的GWAS,已经陆续证实 Phactr1 位点 (6p24) 涉及多种血管疾病的风险,包括冠状动脉疾病、偏头痛、颈动脉夹层、纤维肌肉发育不良和高血压[6]

  • 小鼠体内研究显示,Phactr1 为巨噬细胞中的保护型基因,通过促进M2型巨噬细胞的极化,维持其胞葬作用来抑制动脉粥样硬化的发展[7, 8]。而在内皮细胞中,Phactr1 与内皮细胞炎症、内皮功能障碍及动脉粥样硬化有着千丝万缕的联系[9, 10]。另外,Phactr1 还可调控内皮细胞的增殖、凋亡、迁移、管形成[1, 2, 11]。在血管平滑肌细胞 (Vascular Smooth Muscle Cells,VSMCs) 中,Phactr1 则发挥着促进血管钙化的作用[12]

  • 尽管有诸多GWAS分析显示 Phactr1 与多种血管疾病的易感性显著相关,且部分实验证据也证实了 Phactr1 与炎症、动脉粥样硬化确有联系。但 Phactr1 具体通过哪些机制或生化通路来影响炎症指标和血管钙化等病理生理过程,仍未有一个全面、清晰的解释,Phactr1 作为多血管疾病的共同遗传基础及其分子机制仍需进一步探索。

  • 2 Phactr家族成员、结构域与生物学功能

  • Phactr 家族共有 Phactr 1~4 四个成员,每个PHACTR1蛋白都包含四个Arg-Pro-X-X-X-GluLeu (RPEL) 结构域,分别是一个位于N端的保守RPEL和三个位于C端的RPEL重复序列 (RPEL1-3),两端各存在一个依赖于输入蛋白 ɑ、β 的核输入信号 (B1,B2)。三个C端的RPEL基序用于维持PHACTR1的细胞质定位,其中RPEL3起主要作用。而PHACTR1与胞核内PP1的结合既需要C端RPEL重复序列,也需要C端保守区域[13] (见图1)。

  • 结构分析表明:PHACTR1与PP1的结合重塑了PP1的疏水槽,并在催化位点附近形成了一个新的复合表面。此外,确定了PHACTR1/PP1与其底物Insulin Receptor Tyrosine Kinase Substrate Protein (IRSp53) 和spectrin αⅡ的去磷酸化形式结合的高分辨率结构。由于结合序列的特异性,PHACTR1/PP1对其底物表现出数量级增强的反应性,可以实现有效的去磷酸化[14]。另有研究表明,PHACTR1与PP1相互作用,还可诱导肌球蛋白轻链 (Myosin Light Chain, MLC) 磷酸化和异常的肌球蛋白组装[13]

  • 在C端,每个RPEL结构域都与一个G-actin结合,并通过RPEL基序的次级肌动蛋白接触来控制多价肌动蛋白-RPEL组装的形成[15]。在人脐静脉内皮细胞中敲除 Phactr1,诱导了最初的肌动蛋白解聚,产生了高度扰动的板球动力学、细胞边缘膜动力学的改变,以及管形成的减少[2]。在乳腺癌细胞中高表达 Phactr1,导致肌动蛋白重排和乳腺癌细胞迁移[16]。另有研究也表明,在CHL-1黑色素瘤细胞中,Phactr1 是促进肌动蛋白聚集、瘤细胞运动和侵袭所必需的[13]。总的来说,Phactr1与肌动蛋白的重塑、细胞支持、运动扩张有关。

  • 3 Phactr1与多种心血管疾病的相关性

  • 3.1 偏头痛

  • 偏头痛是一种复发性疼痛疾病,传统上被视为神经血管疾病。通过观察性研究和GWAS的荟萃分析发现,一些遗传变异与偏头痛的易感性有关。研究发现,“细胞质钙离子浓度的积极调节”和“肌醇磷酸介导的信号传导”等途径以及部分中心基因与偏头痛易感性相关,包括Phactr1[17]。在流行病学研究中,偏头痛与冠状动脉疾病的风险增加有关,这表明二者可能存在遗传重叠,有着共同的遗传风险位点。这种共性仅限于非先兆性偏头痛,并且影响方向相反[18]。关联研究发现 Phactr1 的rs9349379是一个显著的共同风险位点[19]。具体说来, rs9349379的G等位基因导致内皮素-1 (Endothe⁃ lin-1, EDN1) 表达升高,EDN1蛋白与VSMCs上的ETA受体结合增加,血管收缩。而偏头痛与颅内和脑膜血管扩张有关,因此单核苷酸多态性 (Single Nucleotide Polymorphism, SNP) rs9349379 (G) 降低了偏头痛的风险[6]

  • 图1 PHACTR家族蛋白序列元件示意图

  • 3.2 颈动脉夹层/自发性冠状动脉夹层

  • 自发性颈动脉夹层是年轻人缺血性卒中的主要原因。一项全基因组研究确定了颈动脉夹层与 Phactr1基因的rs9349379多态性有关。此外,与欧洲血统人群相比,颈动脉夹层风险等位基因rs9349379 (A) 在非洲血统人群中的等位基因频率更高[20]。另一项研究观察到,Phactr1 的rs9349379 (G) 中存在的SNP变异与较低的自发性颈动脉夹层风险相关[21]。这可用以下发现来解释:rs9349379 (G) 促使EDN1蛋白与VSMCs上的内皮素A (En⁃ dothelin A,ETA) 受体结合,促使血管收缩,从而降低了颈动脉夹层的风险[6, 22]

  • 自发性冠状动脉夹层是日益公认的急性冠脉综合征的病因和心肌梗死、心源性猝死的重要病因,主要累及年轻至中年女性[23]。有学者分析了法国、英国、美国和澳大利亚的病例对照研究结果,发现 Phactr1的风险等位基因rs9349379-A与较高的自发性冠状动脉夹层风险相关[22]。另一项荟萃分析发现,Phactr1 的6p24.1染色体、Lrp1 的12q13.3染色体和女性特有染色体21q22.11影响自发性冠状动脉夹层和心肌梗死[24]。此外,在欧洲最大的自发性冠状动脉夹层队列研究中, 45%的病例发现了纤维肌发育不良,且与 Phactr1 的遗传关联得到了证实[25]

  • 3.3 纤维肌发育不良

  • 纤维肌发育不良是一种未被充分认识的非动脉粥样硬化性、非炎性动脉病,最常见于中年女性,但可能影响所有年龄组的个体。这类疾病可能导致狭窄、动脉瘤、夹层、闭塞或动脉弯曲,主要危及肾和脑血管动脉[26]。虽然家族性病例很少见 (< 5%),但有证据表明遗传因素参与这种血管疾病。近来发现的第一个遗传位点 Phactr1,其内含子变异体可影响位于6号染色体附近的EDN1的转录活性[27-29]。在最新的一项全基因组关联分析中,报告了四个强相关性位点:Phactr1Lrp1Atp2b1Lima1。同时,又发现相关变异位于动脉特异性调节元件中,而靶基因广泛参与到肌动蛋白细胞骨架和细胞内钙稳态相关的机制中,这些机制是血管收缩的核心[30]。巧合的是,Phactr1 风险位点对EDN1的远端调控似乎进一步佐证了这一点[6]。最近,纤维肌肉发育不良与 Phactr1 的遗传关联在欧洲的队列研究中也进一步得到了证实[25]

  • 3.4 高血压

  • 目前血压的遗传特征包括30多个基因的突变,罕见的突变导致遗传性的高血压或低血压和1 477个常见的SNP。因此,大多数GWAS鉴定的血压SNP显示出了多效性关联[31]。早先有分析表明 Phactr1的rs9369640和rs599839与高血压有关, T、 C和G等位基因分别具有保护作用[32]。最近一项基因型风险分析显示,Phactr1的rs9349379与高原原发性高血压增加的2.61倍风险相关[33]。然而,又有研究发现rs9349379 (G) 可能发挥了保护性作用。 rs9349379是EDN1的远端调节器,并导致EDN1的表达增加。在大的全身动脉中,EDN1与ETB受体结合,通过产生一氧化氮、前列环素和尿钠排泄来触发内皮依赖性血管舒张,从而降低患高血压的风险[6]

  • 3.5 冠状动脉疾病

  • 冠状动脉疾病是全球最常见的多因素疾病,其特征有内皮损伤、脂质沉积和冠状动脉钙化[34]。一项数据荟萃分析表明,rs9349379多态性与冠状动脉疾病易感性升高相关[35]。在9p21染色体上的SNP和 Phactr1 基因位点与冠状动脉钙化和心梗密切相关,并且与其他冠状动脉钙化和心梗的SNP存在一定的关联[36]。早先,黎巴嫩队列研究中的GWAS证实无论生活方式和种族差异如何,Phactr1 都是冠状动脉狭窄的主要决定因素[37]。此外,另有分析表明 Phactr1 基因多态性与增加墨西哥人群患早发性冠状动脉疾病的风险有关[38]。而从中国汉族人群的GWAS分析中,确定了四个达到全基因组意义的冠状动脉疾病新位点 (在 Ttc32-Wdr35Gucy1a3C6orf10-Btnl2Atp2b1中或附近),并复现了先前在欧洲人群中发现的包括 Phactr1 在内的四个位点[39]。进一步的分析证实了 Phactr1 rs9349379多态性与中国汉族女性人群患冠状动脉疾病的风险增加有关[34]。其中,rs9381439次要等位基因A与中国汉族男性患冠状动脉疾病的风险降低有关[40]。近来一项全基因组关联荟萃分析显示,纤维肌发育不良与更常见的心血管疾病 (包括高血压、偏头痛、颅内动脉瘤和冠状动脉疾病) 之间存在显著的遗传重叠[30]。这意味着这些多血管疾病可能具备共同的遗传基础,其中一种血管疾病的遗传风险位点可能提示其他几种血管疾病的关联SNP。

  • 综上所述, rs9349379的G等位基因的顺式调控效应与较高的EDN1表达和较高的ET-1分泌蛋白有关。rs9349379的G等位基因与冠心病/心肌梗死风险增加、偏头痛、颈动脉夹层、纤维肌肉发育不良和高血压风险降低相关。机制具体说来,ET-1与冠状动脉的ETA受体结合,对VSMCs的影响包括血管收缩、VSMC的增殖、细胞外基质的产生和纤维化,这些下游效应增加冠心病/心肌梗死的风险,降低偏头痛、颈动脉夹层和肌纤维发育不良。另外,ET-1与全身动脉和肾集合系统中的ETB受体结合,通过产生一氧化氮、前列环素和尿钠排泄触发内皮依赖性血管舒张,从而降低高血压的风险[6]

  • 4 Phactr1调控动脉粥样硬化的分子机制

  • 4.1 Phactr1对小鼠动脉粥样硬化的影响

  • 在动脉粥样硬化的小鼠模型中, Phactr 1-/-Apoe-/-小鼠 (双敲除小鼠) 发展出更严重的动脉粥样硬化斑块,并观察到更多的巨噬细胞被招募到内皮下。研究发现,在双敲小鼠骨髓来源的巨噬细胞中,Phactr1 缺陷的巨噬细胞倾向分化为M1表型,通过产生更多的致动脉粥样硬化的促炎细胞因子,最终转化为由氧化低密度脂蛋白 (oxidized Low-Density Lipoprotein, ox-LDL) 驱动的泡沫细胞。从机制上来说,PHACTR1蛋白通过直接与cAMP反应元件结合蛋白 (cAMP-Response Element Binding Protein,CREB) 结合来激活CREB信号传导,进而上调CREB磷酸化并诱导Kruppel-Like Fac⁃ tor 4(KLF4)表达以及促进M2型巨噬细胞的分化,从而减弱动脉粥样硬化的发展[7]

  • 冠状动脉疾病的潜在病因之一是胞葬作用的受损。胞葬作用是指巨噬细胞吞噬并清除凋亡细胞的过程,该过程可防止细胞继发性坏死,抑制炎症并促进炎症消退,从而避免坏死性动脉粥样硬化斑块的形成。研究表明,PHACTR1蛋白可阻止肌球蛋白轻链 (Myosin Light Chain,MLC) 的去磷酸化。与Phactr1的内含子rs9349379-A/A相比,rs9349379-G/G导致巨噬细胞中PHACTR1蛋白表达降低,从而减少磷酸化MLC,进而损害了巨噬细胞的胞葬作用,最终加重了动脉粥样硬化斑块的形成[8]。因此, Phactr1 是通过维持巨噬细胞的胞葬作用来保护机体,从而起到降低动脉粥样硬化及冠状动脉疾病发生的作用。

  • 4.2 Phactr1对巨噬细胞功能的影响

  • 免疫组织化学的证据表明,PHACTR1蛋白在人动脉粥样硬化斑块的巨噬细胞、富含脂质的泡沫细胞、外来淋巴细胞和内皮细胞中高度表达[41]。如前所述,巨噬细胞缺乏 Phactr1 会损害胞葬作用,并促使巨噬细胞向M1型极化,最终促进动脉粥样硬化斑块坏死[7, 8]。此外,研究发现PHACTR1的表达可受到巨噬细胞和内皮细胞中动脉粥样硬化刺激的调节。同样地,在原代人巨噬细胞中发现,冠状动脉的疾病风险SNP rs9349379的风险等位基因与PHACTR1的表达降低相关,类似于炎症刺激的效果[41]。现有的这些证据都提示了 Phactr1 是一个关键的动脉粥样硬化候选基因。

  • 4.3 Phactr1对血管内皮细胞功能的影响

  • 在人脐静脉内皮细胞中,PHACTR1蛋白表达依赖血管内皮生长因子A165 (Vascular Endothelial Growth Factor A165,VEGF-A165),并可能通过与Neuropilin-1 (NRP-1) 和Vascular Endothelial Growth Factor Receptor 1 (VEGF-R1) 两个高亲和力的VEGF-A165受体直接相互作用[2]。另有研究证实,rs9349379处的等位基因与肌细胞增强因子2 (Myocyte Enhancer Factor 2,MEF2) 特异结合[42]。在内皮细胞中敲除 Phactr1 会诱导肌动蛋白解聚,产生高度扰动的板球动力学,最终破坏管的形成[1, 2]。因此,在内皮细胞中,Phactr1 的存在对于肌动蛋白的重塑以及管形成的维持都有着重要的意义。

  • 不仅如此,Phactr1在内皮细胞的增殖、凋亡、迁移中也发挥着重要作用。Phactr1-siRNA处理的细胞通过外在凋亡途径实现细胞凋亡,管形成的破坏也与此相关[1]。同样,在小鼠脑毛细血管内皮细胞中敲低 Phactr1,下调了迁移相关蛋白,包括基质金属蛋白酶2 (Matrix Metallopeptidase2,MMP2) 和MMP-9以及上调凋亡相关蛋白 (包括Bax、 Bcl-2、裂解的半胱天冬酶-3和半胱天冬酶-3) 的表达[11]。有趣的是,在乳腺癌细胞中,也有类似的发现,由转化生长因子 (Transforming Growth Factor-beta, TGF-β) 介导miR-584的沉默表达,导致PHACTR1表达增强,进而加强肌动蛋白重排和促使乳腺癌细胞迁移[16]。基于这些发现,推测在病理条件下,内皮细胞中的 Phactr1 极有可能促使细胞过度增殖、迁移,逐步发展为间充质细胞,促进炎症,加速动脉粥样硬化的进程。

  • 此外,Phactr1 在内皮细胞炎症中也扮演着一个重要角色。研究发现,敲除 Phactr1 诱导了一些与动脉粥样硬化事件有关的因素,如氧化低密度脂蛋白受体、促炎蛋白包括凝血酶、凝血酶受体1 (Protease-Activated Receptor 1,PAR-1)、崩解素和金属蛋白酶结构域 (ADAM-9/-17)、Trombospon⁃ din-2和Galectin-3。并且,PHACTR1表达的下调还可诱导动脉粥样硬化生物标志物的表达,如氨基脲敏感胺氧化酶和TGF-β 诱导基因h3。此外,敲除 Phactr1也下调了MMP调控因子的表达、局灶性粘附激酶 (FAK/PYK2/PAXILLIN),代谢应激途径 (AMPK/CREB/eNOS) 也在内皮细胞中受到抑制[9]

  • 以上这些证据表明 Phactr1 在内皮细胞中发挥着抑炎、抑动脉粥样硬化的作用。然而,更多的证据表明 Phactr1 在内皮细胞中扮演着促炎、促动脉粥样硬化的角色。有实验表明,Phactr1 的位点变异rs9349379,可能通过调节冠状动脉的内皮或VSMCs中 Phactr1 的中间转录本的表达来部分影响冠状动脉疾病[43]。巧合的是,另有研究发现,在主动脉内皮细胞中,oxLDL和肿瘤坏死因子 (Tumour Necrosis Factor-alpha,TNF-α) 都上调了 Phactr1 中间转录本的表达[41]。更有直接证据表明,敲低 Phactr1降低了人冠状动脉内皮细胞中ox-LDL诱导的过量的细胞间粘附分子1 (Intercellular Adhesion Molecule-1,ICAM-1)、血管细胞粘附分子1 (Vas⁃ cular Cell Adhesion Molecule-1,VCAM-1) 和血管内皮钙黏蛋白 (Vascular Endothelial-Cadherin, VE-Cadherin) 的表达,并通过减弱与心肌相关转录因子A (Myocardin-Related Transcription Factor A, MRTF-A)的相互作用来缓解Nuclear Factor-kappa B (NF-κB)/p65的核积累,从而抑制人冠状动脉内皮细胞中的氧化应激和炎症反应[10]。因此,Phactr1对内皮细胞炎症的影响与分子机制值得进一步深入研究。

  • 4.4 PHACTR1对血管平滑肌细胞功能的影响

  • 纵观近年来的研究,关于VSMCs中是否存在 Phactr1 一直存在争议。但总的来看,更多证据提示VSMCs中存在 Phactr1。虽然起初的免疫印迹显示VSMCs中完全没有 PHACTR1 的表达[41],但之后有研究证实PHACTR1蛋白存在于VSMCs中,并存在中间转录本 Phactr1 剪接亚型,可能与冠状动脉疾病相关[43]。此外有研究发现,在小鼠胚胎干细胞衍生的平滑肌细胞中,Phactr1 基因表达随着钙化时间的推移而增加。在钙化的人脐动脉平滑肌细胞中也检测到类似的结果。而敲除 Phactr1,则导致成骨标志物骨桥蛋白 (Osteopontin) 表达降低,过表达 Phactr1 则增强了鼠动脉平滑肌的钙化[12]。因此, Phactr1可在体外VSMCs中调节血管钙化的严重程度,从而与动脉粥样硬化和心肌梗死产生密切联系。

  • 5 讨论与展望

  • 5.1 Phactr1在内皮细胞中对炎症影响的不一致性

  • 如前文所述,在内皮细胞中敲除 Phactr1,可诱导一些与动脉粥样硬化事件有关的因素,以及诱导动脉粥样硬化生物标志物的表达,并抑制代谢应激途径 (AMPK/CREB/eNOS),这些发现显示 Phactr1 在内皮细胞中发挥着抑炎、抑动脉粥样硬化的作用[9]。然而,另有证据显示,Phactr1在内皮细胞中起到促炎、促动脉粥样硬化的作用。例如, oxLDL和TNF-α 都上调了 Phactr1 中间转录本的表达[41]。而敲低 Phactr1 则可降低人冠状动脉内皮细胞中由ox-LDL诱导产生的炎症标志物VCAM-1、 ICAM-1和VE-Cadherin的表达,并通过减弱与MRTF-A的相互作用来缓解NF-κB/p65的核积累,从而抑制细胞中的氧化应激和炎症[10]。基于上述的异质性,也许应在对 Phactr1 进行转录本和基因分型的研究前提下,再探讨 Phactr1 到底在炎症和动脉粥样硬化中扮演着何种角色,如内含子rs9349379-A/G处于非编码区,中间转录本存在促炎性等,或许在各自的转录调控水平存在差异。

  • 5.2 通过 Phactr1 的特异性敲除小鼠验证其对内皮功能的影响

  • 文献已建立的Phactr1-/-Apoe-/-双敲除小鼠模型,探究了全身性 Phactr1 敲除在巨噬细胞中的影响,可能存在非靶向性的作用[7]。由于目前内皮细胞中 Phactr1 对炎症的影响存在不一致性,且对内皮功能的影响尚不明确,因此有必要通过构建 Phactr1 内皮特异性敲除小鼠,来探究 Phactr1 缺陷对内皮功能障碍的影响。另外,可通过体内注射靶向血管内皮细胞的腺相关病毒 (Adeno-Associated Virus, AAV)-Phactr1,使得内皮过表达 Phactr1 来检验 Phactr1对内皮功能的直接影响与分子机制。

  • 5.3 PHACTR1/PP1 复合物对下游信号通路蛋白的去磷酸化

  • PHACTR1作为PP1的互作蛋白,可以与PP1发生直接的相互作用,并将PP1带到细胞中的特定位置,或将靶蛋白递送到PP1上。Fedoryshchak等[14] 使用生物化学方法和X射线晶体学检查了PHACTR1/PP1复合物的结构,物理结构显示PHACTR1与PP1的结合创造了一个新的表面口袋,该口袋可与易受PHACTR1/PP1活性影响的蛋白质的特定序列相互作用。进一步的实验表明,与单独作用的PP1相比,口袋结构使得复合物对其底物蛋白表现出数量级增强的去磷酸化作用[14]。而在内皮细胞中发现,敲除 Phactr1会降低PP1的活性[2]。目前,已知PHACTR1通过结合PP1,可以使PP1定向到与肌动蛋白细胞骨架相关的神经元底物上,从而调节突触活性和树突形态[44]。因此,Phactr1突变可能导致大脑发育过程中皮质神经元的形态和功能发生缺陷,从而导致智力障碍[3]。又有研究表明, PHACTR1通过将PP1连接到Slack通道来调节Slack电流幅值。如若 Phactr1 突变破坏了PP1的结合,便不能改变Slack电流,使得Slack通道与细胞质信号通路耦合失调,则可能引起儿童癫痫相关的智力发育异常[45]。众所周知,磷酸基团的去留,起着 “分子开关”作用,这对于生物代谢调控过程有着重要的意义。目前解析了PHACTR1/PP1与其底物IRSp53和spectrin αⅡ的去磷酸化结合的高分辨率结构,然而,尚未有其他报道关于PHACTR1/PP1复合物对内皮细胞中下游何种信号通路蛋白的去磷酸化发挥作用[14]。这可能需要确定出与复合物口袋结构相互作用的底物特异性序列,才能准确、有效地锚定潜在的底物蛋白。

  • 5.4 Phactr1 基因突变体与多血管疾病的相关性以及基于CRISPR/Cas9的潜在干预

  • 目前,有关 Phactr1 的GWAS分析中,Phactr1 被提及最多的突变位点是6p24,内含子rs9349379 (A/G) 的遗传变异与多种血管疾病显著相关[6]。然而,鉴于分析技术和方法的局限、地域与种族差异、经济条件的限制及研究者的实验设计等因素,尚未知晓 Phactr1 其他全部位点及其他等位基因的突变上是否与多血管疾病存在着潜在的遗传相关性。而对于rs9349379 (A/G) 的遗传变异或未来发现的其他位点上的突变,可以尝试使用CRISPR/Cas9基因编辑技术。目前已有报道通过使用CRISPR/Cas9基因编辑方法,删除了 Phactr1 与MEF-2的结合位点,在携带这种缺失的内皮细胞中,PHACTR1的表达减少了35%[42]。然而,使用基因编辑方法是否可以规避固有的遗传易感性,以及使用这种基因删除技术是否会影响机体正常的生理代谢调控功能,也未可知。鉴于 Phactr1 在多血管疾病中的重要角色地位,其介导血管功能及其机制研究具有重要意义,针对 Phactr1 的调控药物仍需进一步探索。

  • 参考文献

    • [1] JARRAY R,ALLAIN B,BORRIELLO L,et al.Depletion of the novel protein PHACTR-1 from human endothelial cells abolishes tube formation and induces cell death receptor apoptosis[J].Biochimie,2011,93(10):1668-1675.

    • [2] ALLAIN B,JARRAY R,BORRIELLO L,et al.Neuropilin-1 regulates a new vegf-induced gene,phactr-1 which controls tubulogenesis and modulates lamellipodial dynamics in human endothelial cells[J].Cell Signal,2012,24(1):214-223.

    • [3] HAMADA N,OGAYA S,NAKASHIMA M,et al.De novo PHACTR1 mutations in west syndrome and their pathophysiological effects[J].Brain,2018,141(11):3098-3114.

    • [4] MARAKHONOV A V,PŘECHOVÁ M,KONOVALOV FA,et al.Mutation in PHACTR1 associated with multifocal epilepsy with infantile spasms and hypsarrhythmia[J].Clin Genet,2021,99(5):673-683.

    • [5] UITTERLINDEN A G.An introduction to genome-wide association studies:gwas for dummies[J].Semin Reprod Med,2016,34(4):196-204.

    • [6] GUPTA R M,HADAYA J,TREHAN A,et al.A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression[J].Cell,2017,170(3):522-533.

    • [7] LI T,DING L J,WANG Y G,et al.Genetic deficiency of phactr1 promotes atherosclerosis development via facilitating m1 macrophage polarization and foam cell formation[J].Clin Sci(Lond),2020,134(17):2353-2368.

    • [8] KASIKARA C,SCHILPEROORT M,GERLACH B,et al.Deficiency of macrophage phactr1 impairs efferocytosis and promotes atherosclerotic plaque necrosis[J].J Clin Invest,2021,131(8):e145275.

    • [9] JARRAY R,PAVONI S,BORRIELLO L,et al.Disruption of phactr-1 pathway triggers pro-inflammatory and pro-atherogenic factors:new insights in atherosclerosis development[J].Biochimie,2015,118:151-161.

    • [10] ZHANG Z H,JIANG F L,ZENG L X,et al.PHACTR1 regulates oxidative stress and inflammation to coronary artery endothelial cells via interaction with NF-κB/p65[J].Atherosclerosis,2018,278:180-189.

    • [11] JING Y,ZHANG L,XU Z M,et al.Phosphatase actin regulator-1(PHACTR-1)knockdown suppresses cell proliferation and migration and promotes cell apoptosis in the bend.3 mouse brain capillary endothelial cell line[J].Med Sci Monit,2019,25:1291-1300.

    • [12] AHERRAHROU R,AHERRAHROU Z,SCHUNKERT H,et al.Coronary artery disease associated gene phactr1 modulates severity of vascular calcification in vitro[J].Biochem Biophys Res Commun,2017,491(2):396-402.

    • [13] WIEZLAK M,DIRING J,ABELLA J,et al.G-actin regulates the shuttling and pp1 binding of the rpel protein PHACTR1 to control actomyosin assembly[J].J Cell Sci,2012,125(Pt23):5860-5872.

    • [14] FEDORYSHCHAK R O,PŘECHOVÁ M,BUTLER A M,et al.Molecular basis for substrate specificity of the PHACTR1/pp1 phosphatase holoenzyme[J].Elife,2020,9:e61509.

    • [15] MOUILLERON S,WIEZLAK M,O'REILLY N,et al.Structures of the PHACTR1 rpel domain and rpel motif complexes with g-actin reveal the molecular basis for actin binding cooperativity[J].Structure,2012,20(11):1960-1970.

    • [16] FILS-AIMÉ N,DAI M,GUO J,et al.Microrna-584 and the protein phosphatase and actin regulator 1(PHACTR1),a new signaling route through which transforming growth factor-β mediates the migration and actin dynamics of breast cancer cells[J].J Biol Chem,2013,288(17):11807-11823.

    • [17] ZHAO Y T,ZHU R X,XIAO T L,et al.Genetic variants in migraine:a field synopsis and systematic re-analysis of meta-analyses[J].J Headache Pain,2020,21(1):13.

    • [18] FREILINGER T,ANTTILA V,DE VRIES B,et al.Genome-wide association analysis identifies susceptibility loci for migraine without aura[J].Nat Genet,2012,44(7):777-782.

    • [19] WINSVOLD B S,BETTELLA F,WITOELAR A,et al.Shared genetic risk between migraine and coronary artery disease:a genome-wide analysis of common variants[J].PLoS One,2017,12(9):e0185663.

    • [20] GREEN I E,RAHMAN S A,OWENS D L,et al.Cervical artery dissection in patients of african ancestry [J].Cerebrovasc Dis,2018,46(5-6):218-222.

    • [21] ABE A,NITO C,SAKAMOTO Y,et al.Spontaneous bilateral cervical internal carotid and vertebral artery dissection in a japanese patient without collagen vascular disease with special reference to single-nucleotide polymorphisms[J].J Stroke Cerebrovasc Dis,2016,25(8):e114-117.

    • [22] ADLAM D,OLSON T M,COMBARET N,et al.Association of the PHACTR1/EDN1 genetic locus with spontaneous coronary artery dissection[J].J Am Coll Cardiol,2019,73(1):58-66.

    • [23] TURLEY T N,O'BYRNE M M,KOSEL M L,et al.Identification of susceptibility loci for spontaneous coronary artery dissection[J].JAMA Cardiol,2020,5(8):929-938.

    • [24] SAW J,YANG M L,TRINDER M,et al.Chromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction[J].Nat Commun,2020,11(1):4432.

    • [25] COMBARET N,GERBAUD E,DÉRIMAY F,et al.National french registry of spontaneous coronary artery dissections:prevalence of fibromuscular dysplasia and genetic analyses[J].EuroIntervention,2021,17(6):508-515.

    • [26] NARULA N,KADIAN-DODOV D,OLIN J W.Fibromuscular dysplasia:contemporary concepts and future directions[J].Prog Cardiovasc Dis,2018,60(6):580-585.

    • [27] TOUZÉ E,SOUTHERLANDAM,BOULANGER M,et al.Fibromuscular dysplasia and its neurologic manifest-ations:a systematic review[J].JAMA Neurol,2019,76(2):217-226.

    • [28] WARCHOL-CELINSKA E,BERRANDOU T,PREJBISZ A,et al.Genetic study of phactr1 and fibromuscular dysplasia,meta-analysis and effects on clinical features of patients:the arcadia-pol study[J].Hypertension,2020,76(1):e4-e7.

    • [29] KIANDO S R,TUCKER N R,CASTRO-VEGA L J,et al.Phactr1 is a genetic susceptibility locus for fibromuscular dysplasia supporting its complex genetic pattern of inheritance[J].PLoS Genet,2016,12(10):e1006367.

    • [30] GEORGES A,YANG M L,BERRANDOU T E,et al.Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases[J].Nat Commun,2021,12(1):6031.

    • [31] LIP S,PADMANABHAN S.Genomics of blood pressure and hypertension:extending the mosaic theory toward stratification[J].Can J Cardiol,2020,36(5):694-705.

    • [32] FUJIMAKI T,OGURI M,HORIBE H,et al.Association of a transcription factor 21 gene polymorphism with hypertension[J].Biomed Rep,2015,3(1):118-122.

    • [33] LI Z J,HU X,WAN J P,et al.The alleles of agt and hif1a gene affect the risk of hypertension in plateau residents[J].Exp Biol Med(Maywood),2021,246:1-9.

    • [34] CHEN L,QIAN H,LUO Z,et al.Phactr1 gene polymorphism with the risk of coronary artery disease in chinese han population[J].Postgrad Med J,2019,95(1120):67-71.

    • [35] SUN X,SUN J,ZHAO D,et al.Phosphatase and actin regulator 1 rs9349379 polymorphism is associated with an elevated susceptibility to coronary artery disease:a meta-analysis[J].J Biol Regul Homeost Agents,2019,33(3):925-928.

    • [36] O'DONNELL C J,KAVOUSI M,SMITH A V,et al.Genome-wide association study for coronary artery calcification with follow-up in myocardial infarction[J].Circulation,2011,124(25):2855-2864.

    • [37] HAGER J,KAMATANI Y,CAZIER J B,et al.Genome-wide association study in a lebanese cohort confirms phactr1 as a major determinant of coronary artery stenosis [J].PLoS One,2012,7(6):e38663.

    • [38] PÉREZ-HERNÁNDEZ N,VARGAS-ALARCÓN G,POSADAS-SÁNCHEZ R,et al.Phactr1 gene polymorphism is associated with increased risk of developing premature coronary artery disease in mexican population[J].Int J Environ Res Public Health,2016,13(8):803.

    • [39] LU X,WANG L,CHEN S,et al.Genome-wide association study in han chinese identifies four new susceptibility loci for coronary artery disease[J].Nat Genet,2012,44(8):890-894.

    • [40] ZHAO Q,WEI H,LIU D,et al.Phactr1 and slc22a3 gene polymorphisms are associated with reduced coronary artery disease risk in the male Chinese han population[J].Oncotarget,2017,8(1):658-663.

    • [41] RESCHEN M E,LIN D,CHALISEY A,et al.Genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene phactr1[J].Atherosclerosis,2016,250:95-105.

    • [42] BEAUDOIN M,GUPTA R M,WON H H,et al.Myocardial infarction-associated snp at 6p24 interferes with mef2 binding and associates with phactr1 expression levels in human coronary arteries[J].Arterioscler Thromb Vasc Biol,2015,35(6):1472-1479.

    • [43] CODINA-FAUTEUX V A,BEAUDOIN M,LALONDE S,et al.Phactr1 splicing isoforms and eqtls in atherosclerosis-relevant human cells[J].BMC Med Genet,2018,19(1):97.

    • [44] ALLEN P B,GREENFIELD A T,SVENNINGSSON P,et al.Phactrs 1-4:a family of protein phosphatase 1 and actin regulatory proteins[J].Proc Natl Acad Sci U S A,2004,101(18):7187-7192.

    • [45] FLEMING M R,BROWN M R,KRONENGOLD J,et al.Stimulation of slack k(+)channels alters mass at the plasma membrane by triggering dissociation of a phosphatase-regulatory complex[J].Cell Rep,2016,16(9):2281-2288.

  • 参考文献

    • [1] JARRAY R,ALLAIN B,BORRIELLO L,et al.Depletion of the novel protein PHACTR-1 from human endothelial cells abolishes tube formation and induces cell death receptor apoptosis[J].Biochimie,2011,93(10):1668-1675.

    • [2] ALLAIN B,JARRAY R,BORRIELLO L,et al.Neuropilin-1 regulates a new vegf-induced gene,phactr-1 which controls tubulogenesis and modulates lamellipodial dynamics in human endothelial cells[J].Cell Signal,2012,24(1):214-223.

    • [3] HAMADA N,OGAYA S,NAKASHIMA M,et al.De novo PHACTR1 mutations in west syndrome and their pathophysiological effects[J].Brain,2018,141(11):3098-3114.

    • [4] MARAKHONOV A V,PŘECHOVÁ M,KONOVALOV FA,et al.Mutation in PHACTR1 associated with multifocal epilepsy with infantile spasms and hypsarrhythmia[J].Clin Genet,2021,99(5):673-683.

    • [5] UITTERLINDEN A G.An introduction to genome-wide association studies:gwas for dummies[J].Semin Reprod Med,2016,34(4):196-204.

    • [6] GUPTA R M,HADAYA J,TREHAN A,et al.A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression[J].Cell,2017,170(3):522-533.

    • [7] LI T,DING L J,WANG Y G,et al.Genetic deficiency of phactr1 promotes atherosclerosis development via facilitating m1 macrophage polarization and foam cell formation[J].Clin Sci(Lond),2020,134(17):2353-2368.

    • [8] KASIKARA C,SCHILPEROORT M,GERLACH B,et al.Deficiency of macrophage phactr1 impairs efferocytosis and promotes atherosclerotic plaque necrosis[J].J Clin Invest,2021,131(8):e145275.

    • [9] JARRAY R,PAVONI S,BORRIELLO L,et al.Disruption of phactr-1 pathway triggers pro-inflammatory and pro-atherogenic factors:new insights in atherosclerosis development[J].Biochimie,2015,118:151-161.

    • [10] ZHANG Z H,JIANG F L,ZENG L X,et al.PHACTR1 regulates oxidative stress and inflammation to coronary artery endothelial cells via interaction with NF-κB/p65[J].Atherosclerosis,2018,278:180-189.

    • [11] JING Y,ZHANG L,XU Z M,et al.Phosphatase actin regulator-1(PHACTR-1)knockdown suppresses cell proliferation and migration and promotes cell apoptosis in the bend.3 mouse brain capillary endothelial cell line[J].Med Sci Monit,2019,25:1291-1300.

    • [12] AHERRAHROU R,AHERRAHROU Z,SCHUNKERT H,et al.Coronary artery disease associated gene phactr1 modulates severity of vascular calcification in vitro[J].Biochem Biophys Res Commun,2017,491(2):396-402.

    • [13] WIEZLAK M,DIRING J,ABELLA J,et al.G-actin regulates the shuttling and pp1 binding of the rpel protein PHACTR1 to control actomyosin assembly[J].J Cell Sci,2012,125(Pt23):5860-5872.

    • [14] FEDORYSHCHAK R O,PŘECHOVÁ M,BUTLER A M,et al.Molecular basis for substrate specificity of the PHACTR1/pp1 phosphatase holoenzyme[J].Elife,2020,9:e61509.

    • [15] MOUILLERON S,WIEZLAK M,O'REILLY N,et al.Structures of the PHACTR1 rpel domain and rpel motif complexes with g-actin reveal the molecular basis for actin binding cooperativity[J].Structure,2012,20(11):1960-1970.

    • [16] FILS-AIMÉ N,DAI M,GUO J,et al.Microrna-584 and the protein phosphatase and actin regulator 1(PHACTR1),a new signaling route through which transforming growth factor-β mediates the migration and actin dynamics of breast cancer cells[J].J Biol Chem,2013,288(17):11807-11823.

    • [17] ZHAO Y T,ZHU R X,XIAO T L,et al.Genetic variants in migraine:a field synopsis and systematic re-analysis of meta-analyses[J].J Headache Pain,2020,21(1):13.

    • [18] FREILINGER T,ANTTILA V,DE VRIES B,et al.Genome-wide association analysis identifies susceptibility loci for migraine without aura[J].Nat Genet,2012,44(7):777-782.

    • [19] WINSVOLD B S,BETTELLA F,WITOELAR A,et al.Shared genetic risk between migraine and coronary artery disease:a genome-wide analysis of common variants[J].PLoS One,2017,12(9):e0185663.

    • [20] GREEN I E,RAHMAN S A,OWENS D L,et al.Cervical artery dissection in patients of african ancestry [J].Cerebrovasc Dis,2018,46(5-6):218-222.

    • [21] ABE A,NITO C,SAKAMOTO Y,et al.Spontaneous bilateral cervical internal carotid and vertebral artery dissection in a japanese patient without collagen vascular disease with special reference to single-nucleotide polymorphisms[J].J Stroke Cerebrovasc Dis,2016,25(8):e114-117.

    • [22] ADLAM D,OLSON T M,COMBARET N,et al.Association of the PHACTR1/EDN1 genetic locus with spontaneous coronary artery dissection[J].J Am Coll Cardiol,2019,73(1):58-66.

    • [23] TURLEY T N,O'BYRNE M M,KOSEL M L,et al.Identification of susceptibility loci for spontaneous coronary artery dissection[J].JAMA Cardiol,2020,5(8):929-938.

    • [24] SAW J,YANG M L,TRINDER M,et al.Chromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction[J].Nat Commun,2020,11(1):4432.

    • [25] COMBARET N,GERBAUD E,DÉRIMAY F,et al.National french registry of spontaneous coronary artery dissections:prevalence of fibromuscular dysplasia and genetic analyses[J].EuroIntervention,2021,17(6):508-515.

    • [26] NARULA N,KADIAN-DODOV D,OLIN J W.Fibromuscular dysplasia:contemporary concepts and future directions[J].Prog Cardiovasc Dis,2018,60(6):580-585.

    • [27] TOUZÉ E,SOUTHERLANDAM,BOULANGER M,et al.Fibromuscular dysplasia and its neurologic manifest-ations:a systematic review[J].JAMA Neurol,2019,76(2):217-226.

    • [28] WARCHOL-CELINSKA E,BERRANDOU T,PREJBISZ A,et al.Genetic study of phactr1 and fibromuscular dysplasia,meta-analysis and effects on clinical features of patients:the arcadia-pol study[J].Hypertension,2020,76(1):e4-e7.

    • [29] KIANDO S R,TUCKER N R,CASTRO-VEGA L J,et al.Phactr1 is a genetic susceptibility locus for fibromuscular dysplasia supporting its complex genetic pattern of inheritance[J].PLoS Genet,2016,12(10):e1006367.

    • [30] GEORGES A,YANG M L,BERRANDOU T E,et al.Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases[J].Nat Commun,2021,12(1):6031.

    • [31] LIP S,PADMANABHAN S.Genomics of blood pressure and hypertension:extending the mosaic theory toward stratification[J].Can J Cardiol,2020,36(5):694-705.

    • [32] FUJIMAKI T,OGURI M,HORIBE H,et al.Association of a transcription factor 21 gene polymorphism with hypertension[J].Biomed Rep,2015,3(1):118-122.

    • [33] LI Z J,HU X,WAN J P,et al.The alleles of agt and hif1a gene affect the risk of hypertension in plateau residents[J].Exp Biol Med(Maywood),2021,246:1-9.

    • [34] CHEN L,QIAN H,LUO Z,et al.Phactr1 gene polymorphism with the risk of coronary artery disease in chinese han population[J].Postgrad Med J,2019,95(1120):67-71.

    • [35] SUN X,SUN J,ZHAO D,et al.Phosphatase and actin regulator 1 rs9349379 polymorphism is associated with an elevated susceptibility to coronary artery disease:a meta-analysis[J].J Biol Regul Homeost Agents,2019,33(3):925-928.

    • [36] O'DONNELL C J,KAVOUSI M,SMITH A V,et al.Genome-wide association study for coronary artery calcification with follow-up in myocardial infarction[J].Circulation,2011,124(25):2855-2864.

    • [37] HAGER J,KAMATANI Y,CAZIER J B,et al.Genome-wide association study in a lebanese cohort confirms phactr1 as a major determinant of coronary artery stenosis [J].PLoS One,2012,7(6):e38663.

    • [38] PÉREZ-HERNÁNDEZ N,VARGAS-ALARCÓN G,POSADAS-SÁNCHEZ R,et al.Phactr1 gene polymorphism is associated with increased risk of developing premature coronary artery disease in mexican population[J].Int J Environ Res Public Health,2016,13(8):803.

    • [39] LU X,WANG L,CHEN S,et al.Genome-wide association study in han chinese identifies four new susceptibility loci for coronary artery disease[J].Nat Genet,2012,44(8):890-894.

    • [40] ZHAO Q,WEI H,LIU D,et al.Phactr1 and slc22a3 gene polymorphisms are associated with reduced coronary artery disease risk in the male Chinese han population[J].Oncotarget,2017,8(1):658-663.

    • [41] RESCHEN M E,LIN D,CHALISEY A,et al.Genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene phactr1[J].Atherosclerosis,2016,250:95-105.

    • [42] BEAUDOIN M,GUPTA R M,WON H H,et al.Myocardial infarction-associated snp at 6p24 interferes with mef2 binding and associates with phactr1 expression levels in human coronary arteries[J].Arterioscler Thromb Vasc Biol,2015,35(6):1472-1479.

    • [43] CODINA-FAUTEUX V A,BEAUDOIN M,LALONDE S,et al.Phactr1 splicing isoforms and eqtls in atherosclerosis-relevant human cells[J].BMC Med Genet,2018,19(1):97.

    • [44] ALLEN P B,GREENFIELD A T,SVENNINGSSON P,et al.Phactrs 1-4:a family of protein phosphatase 1 and actin regulatory proteins[J].Proc Natl Acad Sci U S A,2004,101(18):7187-7192.

    • [45] FLEMING M R,BROWN M R,KRONENGOLD J,et al.Stimulation of slack k(+)channels alters mass at the plasma membrane by triggering dissociation of a phosphatase-regulatory complex[J].Cell Rep,2016,16(9):2281-2288.

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