药学学报  2016, Vol. 51 Issue (6): 853-859   PDF    
引用本文
HAN Jia-yin, YI Yan, LIANG Ai-hua, ZHANG Yu-shi, LI Chun-ying, WANG Lian-mei, PAN Chen, ZHAO Yong. Research progress of Rho/ROCK signal pathway[J]. Acta Pharm Sin, 2016, 51(6): 853-859.  
韩佳寅, 易艳, 梁爱华, 张宇实, 李春英, 王连嵋, 潘辰, 赵雍. Rho/ROCK信号通路研究进展[J]. 药学学报, 2016, 51(6): 853-859.  
Rho/ROCK信号通路研究进展
韩佳寅, 易艳, 梁爱华 , 张宇实, 李春英, 王连嵋, 潘辰, 赵雍    
中国中医科学院中药研究所, 中药鉴定与安全性检测评估北京市重点实验室, 北京 100700
收稿日期: 2015-10-11; 修回日期: 2015-11-20.
基金项目: 国家科技重大专项资助项目(2015ZX09501004-003-001,2014ZX09304307001,2014ZX09201022-004);国家自然科学基金资助项目(81202993,81374057,81503349);中国中医科学院中药所基本科研业务费自主选题项目(ZZ2014023,ZXKT15031,ZXKT15013);中国中医科学院自选课题项目(Z2014063,Z2014075);中国中医科学院博士研究生创新人才培养基金资助项目(CX201508).
* 通讯作者: liangaihua@sina.com
摘要: Rho GTP酶(Rho GTPase)属于Ras超家族,参与细胞迁移、吞噬、收缩和黏附等活动。ROCK又称Rho激酶(Rho-associated kinase),是目前功能研究最为详细的Rho下游靶效应分子。Rho/ROCK信号通路诱导细胞骨架重组、细胞迁移和应力纤维形成,与内皮通透性、组织收缩和生长等多种生理功能有关,参与糖尿病肾病、眼疾病、肿瘤、心脏病、神经损伤性疾病、高血压、辐射损伤和白血病等疾病的发生,作为药物研发靶点越来越得到人们的关注。本文主要针对Rho/ROCK信号通路的基本生物学特征、生理学作用与疾病的相关性和作为治疗靶点的治疗方法研究等进行综述。
关键词: Rho GTP 酶     Rho     Rho 激酶     信号通路    
Research progress of Rho/ROCK signal pathway
HAN Jia-yin, YI Yan, LIANG Ai-hua , ZHANG Yu-shi, LI Chun-ying, WANG Lian-mei, PAN Chen, ZHAO Yong    
Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
Abstract: Rho GTPases belong to Ras superfamily, which is reported to involve in cell migration, phagocytosis, contraction and adhesion. ROCK (also known as Rho-associated kinase) is considered to be one of the most important downstream targets of Rho that is widely investigated. Rho/ROCK signal pathway induces cytoskeletal reorganization, cell migration and stress fiber formation, affects endothelial permeability, tissue constriction and growth, involves in diabetic nephropathy, eye disease, cancer, heart disease, nerve injury disease, hypertension, radiation injury and leukemia. As a novel drug research target, Rho/ROCK signal pathway has received more and more attention. This review provides the basic characteristics and physiological effects of Rho/ROCK signal pathway, the relationships between Rho/ROCK signal pathway and diseases, and the therapeutic methods based on the Rho/ROCK signal pathway.
Key words: Rho GTPase     Rho     Rho-associated kinase     signal pathway    

Rho GTP酶 (Rho GTPase) 于1985年被发现,属于Ras超家族,与Ras有25% 的同源性。Rho (A、B、C) 是Rho GTP酶最主要的成员之一。ROCK又称Rho激酶 (Rho-associated kinase),是目前功能研究最为详细的Rho下游靶效应分子。研究发现Rho/ROCK信号通路诱导细胞骨架重组、细胞迁移和应力纤维形成,与血管和组织通透性、组织收缩和生长等多种生理功能有关。糖尿病肾病、眼疾病、肿瘤、心脏病、神经损伤性疾病、高血压、辐射损伤和白血病等疾病的发生均与Rho/ROCK信号通路的激活有关。因此该通路作为药物研发靶点越来越得到人们的关注。

1 Rho/ROCK信号通路基本生物学特征 1.1 Rho GTP酶与Rho

目前发现的分布在哺乳动物组织细胞中的Rho GTP酶成员主要有Rho (A、B、C)、Rac (1、2、3)、Cdc42 (Cdc42Hs/G25K、TC10、Tcl)、RhoD、RhoG、Chp (1、2)、Rnd (RhoE/Rnd3、Rnd1/Rho6、Rnd2/Rho7)、RhoH/TTF、Rif、Wrch1和RhoBTB (1、2),目前研究最多的是Rho、Rac和Cdc42三类。Rho GTP酶参与细胞迁移、吞噬、收缩和黏附等活动。其中Rho可以促进应力纤维形成和伸长、肌动蛋白束收缩和定向粘连; Rac和Cdc42则主要诱导片状伪足和丝足形成,促进突出活动[1, 2]。

1.2 ROCK

ROCK又称Rho激酶(Rho-associated kinase),属于丝氨酸/苏氨酸蛋白激酶,分子质量大约160 kD,是目前功能研究最为详细的Rho下游靶效应分子。ROCK具有调节细胞收缩、迁移、黏附和增殖等多种功能[3]。药理学研究发现糖尿病肾病、癌 症、高血压、神经损伤和青光眼等多种疾病的发生 与ROCK有关。ROCK氨基酸序列由激酶催化结构域 (kinase domain,RBD) (氨基端)、盘旋螺旋域 (coiled-coil region)、PH结构域 (pleckstrin homology,PH) 和半胱氨酸富集结构域(cysteine-rich domain,CRD) (羧基端) 组成,其中Rho结合域 (Rho-binding domain,RBD) 在盘旋螺旋域内[4]。ROCK包括ROCK1 (ROKβ,p160-ROCK) 和ROCK2 (ROKα) 亚型,两种亚型的氨基酸序列一致性为65%,在激酶结构域有高度相似性 (92%一致)[5]。ROCK分布于全身组织,相比较而言,ROCK1在非神经组织 (肝、肺、脾和睾丸) 中有更高表达,而ROCK2在脑、心脏和肌肉中有更高表达。基因沉默实验结果显示,ROCK1在应力纤维形成中起关键作用,而ROCK2在吞噬和细胞收缩中起重要作用[3, 6]。

1.3 Rho/ROCK信号通路生物学作用

Rho有与GDP结合失活和与GTP结合激活两种状态,两种状态的相对比例受GTP酶激活蛋白 (GTPase activating proteins,GAP) 和鸟苷酸交换因子 (guanine nucleotide exchange factors,GEF) 共同调节。Rho/ROCK信号 通路通过Rho与GTP结合激活下游ROCK,并进一步磷酸化ROCK下游底物,重塑细胞骨架、诱导肌动蛋白丝稳定和肌动蛋白−肌球蛋白收缩、组合肌动蛋白网和肌球蛋白纤维、调节微管动力 (图 1)。ROCK主要下游底物及其磷酸化后导致的效应如表 1[3, 4, 7]所示。

Figure 1 Rho-ROCK Targets

Table 1 Main substrates of ROCK and effects of phosphorylation[3,4,7]
2 Rho/ROCK信号通路的生理学作用 2.1 Rho/ROCK信号通路对血管和组织内皮通透性的影响

受到组胺、凝血酶、血管内皮生长因子、脂多糖和机械作用等刺激时RhoA会激活,激活的RhoA与ROCK结合后,增加钙调蛋白形成,上调细胞内Ca2+浓度,使肌球蛋白轻链激酶 (myosin light chain kinase,MLCK) 活化,上调磷酸化肌球蛋白轻链 (phospho-myosin light chain,p-MLC) 水平; 同时,磷酸化肌球蛋白轻链磷酸酶 (myosin light chain phosphatase,MLCP),抑制p-MLC去磷酸化,导致血管内皮通透性增加,屏障作用减弱[8, 9, 10, 11]。ROCK对淋巴内皮通透性的作用与血管内皮不同,在受到组胺和凝血酶刺激时,ROCK可以保护淋巴内皮屏障的完整性,降低增高的淋巴内皮通透性[12]。此外,Rho在调控肌动蛋白骨架中起到重要作用,可以调节E-钙黏着蛋白介导的细胞间黏附连接,影响上皮组织功能。E-钙黏着蛋白可以诱导Rac活化,初期Rac活化引起p190RhoGAP活化而抑制RhoA活性,随后Rac活性逐渐被RhoA取代,形成成熟的细胞间黏附连接[13]。受到酒精刺激时,肠内Rho/ROCK信号通路激活,导致肠通透性增加,屏障功能受损[14]。Rho/ROCK信号通路激活可以分解紧密连接,参与TGF-β1诱导的肾小管上皮−间充质转分化[15]。

2.2 Rho/ROCK信号通路对组织收缩的影响

Rho/ ROCK信号通路激活可以诱导组织对Ca2+敏感性增加,增强平滑肌细胞收缩。豚鼠吸入卵清蛋白和组胺等刺激物后,气道平滑肌收缩明显增高,同时肺匀浆中RhoA表达增加[16]。感染引起的新生儿早产与Rho/ ROCK信号通路激活有关,体外研究发现,ROCK抑制剂可以明显减弱脂多糖刺激引起的子宫肌层细胞收缩[17]。此外,Rho/ROCK信号通路激活可以诱导MLCP和MLC磷酸化,增加血管平滑肌细胞收缩,ROCK2是该过程中起主导作用的亚型[18]。

2.3 Rho/ROCK信号通路对组织生长的作用

ROCK2通过调节黏着斑形成和成熟而调节成肌细胞定向移动,对骨骼肌的生长和再生起重要作用。ROCK2被抑制时,成肌细胞的迁移速度加快,方向性减弱,使黏着斑成熟受到抑制[19]。Rho/ROCK信号通路激活能介导纤维原细胞收缩,在创伤愈合的增殖期中促进愈合[20]。Rho/ROCK信号通路与神经元伸展、收缩、死亡,神经轴突变性和损伤后再生长相关[21]。抑制Rho/ROCK信号通路可抑制神经胶质生长抑制因子活性,促进受损神经轴突生长[22],ROCK2是该过程中起主导作用的亚型[23]。Rho/ROCK信号通路与骨髓间质干细胞透过血脑屏障有关,抑制该通路可以促进细胞的跨膜转运[24]。

3 Rho/ROCK信号通路与疾病 3.1 糖尿病肾病

高糖可以激活系膜细胞内Rho/ ROCK信号通路,活化转录因子AP-1,上调纤连蛋白,导致肾小球基质蛋白累积[25]。Rho/ROCK信号通路激活可以调节NF-κB信号通路,上调炎症基因并诱导糖尿病肾病的发生[26]。ROCK抑制剂可以减少促硬化细胞因子和细胞外基质,抗氧化并保护线粒体,从而降低糖尿病肾病中硬化和纤维化的发展速度,抑制肾小球通透性,保护肾脏[27]。

3.2 眼疾病

大多数视网膜疾病中视网膜-血液屏障受损,使血液中的凝血酶与视网膜色素上皮直接接触,凝血酶进而激活Rho/ROCK信号通路促进肌动蛋白应力纤维形成和MLC磷酸化,诱导视网膜色素上皮细胞转化和迁移,导致视网膜−血液屏障功能障碍[28]。高糖可以通过激活Rho/ROCK信号通路影响紧密连接,使微血管内皮细胞屏障功能受损,诱发糖尿病视网膜病变[29]。Rho/ROCK信号通路参与青光眼的发生,抑制该通路从而促使小梁网放松,增加房水流动,降低眼压; 抑制球筋膜囊成纤维细胞转分化为肌成纤维细胞; 保护眼神经和增加血液流动; 提高视网膜神经节细胞存活和轴突再生[30]。

3.3 肿瘤

Rho/ROCK信号通路对生物膜通透性的影响会影响癌细胞的转移[31],抑制ROCK可以减少肺癌、乳房癌、肝癌、胃癌和腹部动脉瘤等肿瘤细胞的侵入和转移[32, 33]。Ras/Rho/ROCK信号通路可以通过影响蛋白水解酶类分泌而影响溶血磷酸酯诱发卵巢癌的发展[34]。人非小细胞肺癌DEK原癌基因耗竭时RhoA/ROCK信号通路关键蛋白表达明显降低[35]。

3.4 心脏病

RhoA/ROCK信号通路激活可以增加局部缺血心肌纤维化水平,急性心肌纤维化大鼠心脏组织的RhoA和ROCK表达明显增高[36]。Rho/ROCK信号通路参与NAD(P)H氧化酶激活,诱导氧化应激,诱发心脏微血管损伤[37]和C反应蛋白诱导的动脉粥样硬化血栓。C反应蛋白还可以通过该信号通路的激活增加NF-κB活性,上调动脉粥样硬化血栓基因PAI-1转录和表达[38]。高糖可以激活Rho/ROCK通路,诱导内脏脂肪素和I型前胶原在成心肌细胞的表达,使成心肌细胞过增殖而诱发糖尿病心肌病[39]。ROCK抑制剂可以改善血管平滑肌细胞过收缩、内皮功能障碍、炎症细胞浸润、血管和心肌重构等状况,起到保护心脏的作用[40]。他汀类药物降低血清胆固醇含量、提高内皮功能、减少血管炎症反应从而治疗动脉粥样硬化的作用也与抑制Rho/ROCK信号通路有关[41]。

3.5 神经损伤性疾病

Rho/ROCK信号通路被发现参与脊髓损伤、创伤性脑损伤和阿尔兹海默症等多种神经损伤类疾病[42]。脊髓损伤时,Rho活化,从而诱发生长锥萎缩导致轴突再生障碍,同时诱发硫酸软骨素蛋白聚糖对神经元生长的抑制作用。C3转移酶可以通过抑制Rho,促进轴突生长[43]。

3.6 高血压

ROCK激活可以诱导肺组织对Ca2+敏感性增加,使肺血管持续收缩,引起肺性高血压和肺功能异常[44]。对原发性高血压患者皮肤组织进行分析,发现ROCK表达上调导致的功能性血管收缩与发病有明显相关性[45]。

3.7 辐射损伤

Rho/ROCK信号通路激活可以诱导肌动蛋白磷酸化,引发细胞纤维化。体内和体外实验结果均证明,暴露于辐射一段时间后造成的心肺生理和病理损伤与该通路参与诱导的纤维化有关[46]。电离辐射导致的内皮黏附纤连蛋白和焦点黏着形成、内皮细胞迁移减少、内皮功能障碍与Rho/ROCK信号通路激活诱导的肌动蛋白骨架重组和应力纤维形成有关[47]。

3.8 白血病

RhoA是慢性髓细胞样白血病多形核白细胞功能缺陷和肌动蛋白聚合的重要调节分子。实验证实,对于正常多形核白细胞,Ras是调节肌动蛋白聚合的主要分子; 而对于慢性髓细胞样白血病多形核白细胞,RhoA起主要调节作用。抑制RhoA/ ROCK信号通路可以抑制慢性髓细胞样白血病细胞系生长[48]。

4 以Rho/ROCK信号通路为治疗靶点的治疗方法研究 4.1 激活Rho/ROCK信号通路的治疗方法

脂连素可以通过激活Rho/ROCK信号通路调节肌动蛋白细胞骨架重组而增加葡萄糖摄入,从而调节葡萄糖和脂肪酸的代谢达到保护心脏的作用[49]。

4.2 抑制Rho/ROCK信号通路的治疗方法

ROCK抑制剂Y27632可以在肺移植后缺血再灌注肺损伤中抑制炎症细胞迁移到肺泡腔,减少TNF-α生成,减轻水肿[50]; 在体外实验中通过减少黑色素瘤细胞板状伪足并增加丝状伪足减少肿瘤细胞的侵入和存活能力,在体内实验中减少肿瘤体积[51]。

ROCK抑制剂法舒地尔可以减弱化学物质的肾毒性,保护受损的肾小管,减少细胞因子生成[52],抑制肾结石形成和分布,减轻肾纤维化[53],从而减少肾损伤,提高肾功能; 抑制炎性因子、凋亡因子、纤维化因子、分裂素活性蛋白酶和氮氧化通路,改善肾病状况[54]; 减少VCAM-1和MCP-1在内皮的表达,减弱高糖诱导的单核内皮细胞黏着,防护糖尿病相关的血管炎症和动脉粥样硬化[55]; 抑制VEGF诱导的内皮细胞迁移和MLC磷酸化,减少应力纤维形成和粘着斑配置,从而抑制肿瘤发生[56]。新型特异性ROCK2抑制剂FSD-C10在诱导神经轴突生长、BV-2小神经胶质细胞网形成,促进脑源性和神经胶质细胞系神经营养因子产生方面与法舒地尔有相似的效果,而在致血管舒张方面比法舒地尔有更少的不良反应[57]。

ROCK抑制剂DL0805-2可以阻断AngII诱导的MLC磷酸化增加和p-MLC去磷酸化抑制,促进离体小动脉舒张[58]。

ROCK抑制剂L-F001可以抗氧化应激、清除活性氧和降低细胞内谷胱甘肽水平,通过改善线粒体功能损伤和内质网应激从而减少百草枯导致的细胞损伤和死亡,有可能成为治疗帕金森和神经退行性病变引发疾病的新药[59]。

ROCK酶活性抑制剂GSK269962A和SB-7720770- B可以抑制炎性因子的产生、舒张收缩动脉血管和降低自发性高血压大鼠血压,有潜力成为治疗心血管疾病的新药[60]。

酪氨酸激酶抑制剂dasatinib可以抑制黏着斑形成和肌动球蛋白收缩,减少Müller细胞基质收缩,从而减少视网膜外膜收缩[61]。

5 展望

近年来研究发现Rho/ROCK信号通路激活与糖尿病肾病、眼疾病、肿瘤、心脏病和神经损伤性疾病的发生发展密切相关,以该通路作为疾病的治疗靶点越来越得到人们的广泛关注。由于Rho、ROCK在体内分布广泛,涉及生理功能复杂,因此以该通路作为靶点的药物潜在不良反应较大,很少能够真正在临床上得到应用。目前已经在临床上应用的以Rho/ ROCK信号通路作为靶点的药物仅有法舒地尔和Y27632两种小分子ROCK非特异性抑制剂,且这两种药物在应用时会一定程度地引起患者出现颅内出血、白细胞减少和肝肾功能影响等不良反应[62]。虽然对于Rho/ROCK信号通路已有较多研究,但是还有许多问题有待进一步解决。如Rho/ROCK信号通路下游因子活化后的生理功能,该通路与其他信号通路的交互作用,Rho/ROCK信号通路在不同组织细胞中的不同作用,不同抑制剂作用信号通路靶点不同而导致的不同生理功能影响等都需进一步研究阐明。深入研究Rho/ROCK信号通路的生理功能和与疾病的相关性,对开发有针对性疗效、吸收好、不良反应少的新靶点药物,有重要的理论意义。

参考文献
[1] Wojciak-Stothard B, Ridley AJ. Rho GTPases and the regulation of endothelial permeability[J]. Vascul Pharmacol, 2002, 39:187-199.
[2] Guo W, Meng JZ, Chen Y. Rho/Rho-kinase signalling pathways and vascular endothelial permeability[J]. J Biomed Eng Res (生物医学工程研究), 2009, 28:154-158.
[3] Amano M, Nakayama M, Kaibuchi K. Rho-kinase/ROCK:A key regulator of the cytoskeleton and cell polarity[J]. Cytoskeleton, 2010, 67:545-554.
[4] Riento K, Ridley AJ. Rocks:multifunctional kinases in cell behaviour[J]. Nat Rev Mol Cell Biol, 2003, 4:446-456.
[5] Li Q, Li XY, Liu AL. The research progress of Rhoassociated kinase in physiology and pathophysiology[J]. Chin Pharm J (中国药学杂志), 2011, 46:1860-1864.
[6] Morgan-Fisher M, Wewer UM, Yoneda A. Regulation of ROCK activity in cancer[J]. J Histochem Cytochem, 2013, 61:185-198.
[7] Amin E, Dubey BN, Zhang SC, et al. Rho-kinase:regulation, (dys)function, and inhibition[J]. Biol Chem, 2013, 394:1399-1410.
[8] Kumar P, Shen Q, Pivetti CD, et al. Molecular mechanisms of endothelial hyperpermeability:implications in inflammation[J]. Expert Rev Mol Med, 2009, 11:e19.
[9] Chen SC, Liu CC, Huang SY, et al. Vascular hyperpermeability in response to inflammatory mustard oil is mediated by Rho kinase in mice systemically exposed to arsenic[J]. Microvasc Res, 2011, 82:182-189.
[10] Yu Y, Qin J, Liu M, et al. Role of Rho kinase in lysophosphatidic acid-induced altering of blood-brain barrier permeability[J]. Int J Mol Med, 2014, 33:661-669.
[11] Bogatcheva NV, Zemskova MA, Poirier C, et al. The suppression of myosin light chain (MLC) phosphorylation during the response to lipopolysaccharide (LPS):beneficial or detrimental to endothelial barrier[J]. J Cell Physiol, 2011, 226:3132-3146.
[12] Breslin JW. ROCK and cAMP promote lymphatic endothelial cell barrier integrity and modulate histamine and thrombininduced barrier dysfunction[J]. Lymphat Res Biol, 2011, 9:3-11.
[13] Nakahara S, Tsutsumi K, Zuinen T, et al. FilGAP, a Rho-ROCK-regulated GAP for Rac, controls adherens junctions in MDCK cells[J]. J Cell Sci, 2015, 128:2047-2056.
[14] Elamin E, MascleeA, Dekker J, et al. Ethanol disrupts intestinal epithelial tight junction integrity through intracellular calcium-mediated Rho/ROCK activation[J]. Am J Physiol Gastrointest Liver Physiol, 2014, 306:G677-G685.
[15] Zhang K, Zhang H, Xiang H, et al. TGF-β1 induces the dissolution of tight junctions in human renal proximal tubular cells:role of the RhoA/ROCK signaling pathway[J]. Int J Mol Med, 2013, 32:464-468.
[16] Schaafsma D, Gosens R, Bos IS, et al. Allergic sensitization enhances the contribution of Rho-kinase to airway smooth muscle contraction[J]. Br J Pharmacol, 2004, 143:477-484.
[17] Hutchinson JL, Rajagopal SP, Yuan M, et al. Lipopolysaccharide promotes contraction of uterine myocytes via activation of Rho/ROCK signaling pathways[J]. FASEB J, 2014, 28:94-105.
[18] Wang Y, Zheng XR, Riddick N, et al. ROCK isoform regulation of myosin phosphatase and contractility in vascular smooth muscle cells[J]. Circ Res, 2009, 104:531-540.
[19] Goetsch KP, Snyman C, Myburgh KH, et al. ROCK-2 is associated with focal adhesion maturation during myoblast migration[J]. J Cell Biochem, 2014, 115:1299-1307.
[20] Nobe K, Nobe H, Yoshida H, et al. Rho A and the Rho kinase pathway regulate fibroblast contraction:enhanced contraction in constitutively active Rho A fibroblast cells[J]. Biochem Biophys Res Commun, 2010, 399:292-299.
[21] Tan HB, Zhong YS, Cheng Y, et al. Rho/ROCK pathway and neural regeneration:a potential therapeutic target for central nervous system and optic nerve damage[J]. Int J Ophthalmol, 2011, 4:652-657.
[22] Roloff F, Scheiblich H, Dewitz C, et al. Enhanced neurite outgrowth of human model (NT2) neurons by small-molecule inhibitors of Rho/ROCK signaling[J]. PLoS One, 2015, 10:e0118536.
[23] Koch JC, Tönges L, Barski E, et al. ROCK2 is a major regulator of axonal degeneration, neuronal death and axonal regeneration in the CNS[J]. Cell Death Dis, 2014, 5:e1225.
[24] Lin MN, Shang DS, Sun W, et al. Involvement of PI3K and ROCK signaling pathways in migration of bone marrow-derived mesenchymal stem cells through human brain microvascular endothelial cell monolayers[J]. Brain Res, 2013, 1513:1-8.
[25] Peng F, Wu D, Gao B, et al. RhoA/Rho-kinase contribute to the pathogenesis of diabetic renal disease[J]. Diabetes, 2008, 57:1683-1692.
[26] Xie X, Peng J, Huang K, et al. Activation of RhoA/ROCK regulates NF-κB signaling pathway in experimental diabetic nephropathy[J]. Mol Cell Endocrinol, 2013, 369:86-97.
[27] Komers R. Rho kinase inhibition in diabetic nephropathy[J].Curr Opin Nephrol Hypertens, 2011, 20:77-83.
[28] Ruiz-Loredo AY, López E, López-Colomé AM. Thrombin promotes actin stress fiber formation in RPE through Rho/ROCK-mediated MLC phosphorylation[J]. J Cell Physiol, 2011, 226:414-423.
[29] Lu QY, Chen W, Lu L, et al. Involvement of RhoA/ROCK1 signaling pathway in hyperglycemia-induced microvascular endothelial dysfunction in diabetic retinopathy[J]. Int J Clin Exp Pathol, 2014, 7:7268-7277.
[30] Wang J, Liu X, Zhong Y. Rho/Rho-associated kinase pathway in glaucoma (Review)[J]. Int J Oncol, 2013, 43:1357-1367.
[31] Wilhelm I, Fazakas C, Molnár J, et al. Role of Rho/ROCK signaling in the interaction of melanoma cells with the bloodbrain barrier[J]. Pigment Cell Melanoma Res, 2014, 27:113-123.
[32] Matsuoka T, Yashiro M. Rho/ROCK signaling in motility and metastasis of gastric cancer[J]. World J Gastroenterol, 2014, 20:13756-13766.
[33] Tsai SH, Huang PH, Peng YJ, et al. Zoledronate attenuates angiotensin II-induced abdominal aortic aneurysm through inactivation of Rho/ROCK-dependent JNK and NF-κB pathway[J]. Cardiovasc Res, 2013, 100:501-510.
[34] Jeong KJ, Park SY, Cho KH, et al. The Rho/ROCK pathway for lysophosphatidic acid-induced proteolytic enzyme expression and ovarian cancer cell invasion[J]. Oncogene, 2012, 31:4279-4289.
[35] Wang J, Sun L, Yang M, et al. DEK depletion negatively regulates Rho/ROCK/MLC pathway in non-small cell lung cancer[J]. J Histochem Cytochem, 2013, 61:510-521.
[36] Gao HC, Zhao H, Zhang WQ, et al. The role of the Rho/Rock signaling pathway in the pathogenesis of acute ischemic myocardial fibrosis in rat models[J]. Exp Ther Med, 2013, 5:1123-1128.
[37] Ge GH, Dou HJ, Yang SS, et al. Glucagon-like peptide-1 protects against cardiac microvascular endothelial cells injured by high glucose[J]. Asian Pac J Trop Med, 2015, 8:73-78.
[38] Hung CN, Huang HP, Wang CJ, et al. Sulforaphane inhibits TNF-α-induced adhesion molecule expression through the Rho A/ROCK/NF-κB signaling pathway[J]. J Med Food, 2014, 17:1095-1102.
[39] Yang R, Chang L, Liu S, et al. High glucose induces Rho/ROCK-dependent visfatin and type I procollagen expression in rat primary cardiac fibroblasts[J]. Mol Med Rep, 2014, 10:1992-1998.
[40] Shi J, Wei L. Rho kinases in cardiovascular physiology and pathophysiology:the effect of fasudil[J]. J Cardiovasc Pharmacol, 2013, 62:341-354.
[41] Sawada N,Liao JK. Rho/Rho-associated coiled-coil forming kinase pathway as therapeutic targets for statins in atherosclerosis[J]. Antioxid Redox Signal, 2014, 20:1251-1267.
[42] Raad M, EI Tal T, Gul R, et al. Neuroproteomics approach and neurosystems biology analysis:ROCK inhibitors as promising therapeutic targets in neurodegeneration and neurotrauma[J]. Electrophoresis, 2012, 33:3659-3668.
[43] Forgione N, Fehlings MG. Rho-ROCK inhibition in the treatment of spinal cord injury[J]. World Neurosurg, 2014, 82:e535-e539.
[44] Nagaoka T, Gebb SA, Karoor V, et al. Involvement of RhoA/Rho kinase signaling in pulmonary hypertension of the fawn-hooded rat[J]. J Appl Physiol, 2006, 100:996-1002.
[45] Smith CJ, Santhanam L, Alexander LM. Rho-kinase activity and cutaneous vasoconstriction is upregulated in essential hypertensive humans[J]. Microvasc Res, 2013, 87:58-64.
[46] Monceau V, Pasinetti N, Schupp C. Modulation of the Rho/ROCK pathway in heart and lung after thorax irradiation reveals targets to improve normal tissue toxicity[J]. Curr Drug Targets, 2010, 11:1395-1404.
[47] Rousseau M, Gaugler MH, Rodallec A, et al. RhoA GTPase regulates radiation-induced alterations in endothelial cell adhesion and migration[J]. Biochem Biophys Res Commun, 2011, 414:750-755.
[48] Molli PR, Pradhan MB, Advani SH, et al. RhoA:a therapeutic target for chronic myeloid leukemia[J]. Mol Cancer, 2012, 11:16.
[49] Palanivel R, Ganguly R, Turdi S, et al. Adiponectin stimulates Rho-mediated actin cytoskeleton remodeling and glucose uptake via APPL1 in primary cardiomyocytes[J]. Metabolism, 2014, 63:1363-1373.
[50] Kohno M, Watanabe M, Goto T, et al. Attenuation of lung ischemia-reperfusion injury by rho-associated kinase inhibition in a rat model of lung transplantation[J]. Ann Thorac Cardiovasc Surg, 2014, 20:359-364.
[51] Routhier A, Astuccio M, Lahey D, et al. Pharmacological inhibition of Rho-kinase signaling with Y-27632 blocks melanoma tumor growth[J]. Oncol Rep, 2010, 23:861-867.
[52] Nozaki Y, Kinoshita K, Hino S, et al. Signaling Rho-kinase mediates inflammation and apoptosis in T cells and renal tubules in cisplatin nephrotoxicity[J]. Am J Physiol Renal Physiol, 2015, 308:F899-F909.
[53] Hu H, Chen W, Ding J, et al. Fasudil prevents calcium oxalate crystal deposit and renal fibrogenesis in glyoxylateinduced nephrolithic mice[J]. Exp Mol Pathol, 2015, 98:277-285.
[54] Park JW, Park CH, Kim IJ, et al. Rho kinase inhibition by fasudil attenuates cyclosporine-induced kidney injury[J]. J Pharmacol Exp Ther, 2011, 338:271-279.
[55] Li H, Peng W, Jian W, et al. ROCK inhibitor fasudil attenuated high glucose-induced MCP-1 and VCAM-1 expression and monocyte-endothelial cell adhesion[J]. Cardiovasc Diabetol, 2012, 11:65.
[56] Yin L, Morishige K, Takahashi T, et al. Fasudil inhibits vascular endothelial growth factor-induced angiogenesis in vitro and in vivo[J]. Mol Cancer Ther, 2007, 6:1517-1525.
[57] Xin YL, Yu JZ, Yang XW, et al. FSD-C10:a more promising novel ROCK inhibitor than Fasudil for treatment of CNS autoimmunity[J]. Biosci Rep, 2015. DOI:10.1042/BSR20150032.
[58] Yuan TY, Yan Y, Wu YJ, et al. Vasodilatory effect of a novel Rho-kinase inhibitor, DL0805-2, on the rat mesenteric artery and its potential mechanisms[J]. Cardiovasc Drugs Ther, 2014, 28:415-424.
[59] Shen W, Wang L, Pi R, et al. L-F001, a multifunctional ROCK inhibitor prevents paraquat-induced cell death through attenuating ER stress and mitochondrial dysfunction in PC12 cells[J]. Biochem Biophys Res Commun, 2015, 464:794-799.
[60] Doe C, Bentley R, Behm DJ, et al. Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities[J]. J Pharmacol Exp Ther, 2007, 320:89-98.
[61] Tsukahara R, Umazume K, Yamakawa N, et al. Dasatinib affects focal adhesion and myosin regulation to inhibit matrix contraction by Muller cells[J]. Exp Eye Res, 2015, 139:90-96.
[62] Ai NN, Li S, Zhong CM, et al. Recent advances of Rhoassociated protein kinase (ROCK) in cardio-cerebrovascular diseases[J]. Prog Mod Biomed (现代生物医学进展), 2015, 15:4198-4200.
Rho/ROCK信号通路研究进展
韩佳寅, 易艳, 梁爱华 , 张宇实, 李春英, 王连嵋, 潘辰, 赵雍