药学学报

Drug	Side effect
Glucocorticoid	Diabetes, osteoporosis, serious infection, thrombotic stroke, and death
NSAIDs
Aspirin and celecoxib	Gastrointestinal reaction, renal injury, hepatotoxicity, respiratory tract inflammation, and infection
csDMARDs
Methotrexate	Hepatotoxicity, nephrotoxicity, and carcinogenicity
Sulfasalazine	Hepatitis, thrombocytopenia, proteinuria, and drug-induced lupus erythematosus
Leflunomide	Urticaria, oral ulcers, leukocytopenia, interstitial lung disease, and hypertension
bDMARDs
Etanercept	Cellulitis, increase in liver enzymes, thrombocytopenia, pneumonia, urogenital tract infection, and demyelination
Tocilizumab	Hyperlipidaemia, neutropenia, and hypersensitivity reaction
Rituximab	Hypersensitivity reactions, dyspepsia, pancytopenia, bronchial spasms, and temporary hyperuricemia
Abatacept	Rash, hyperlipidaemia, leukopenia, bronchitis, urogenital tract infection, and headaches

Drug	Side effect
Glucocorticoid	Diabetes, osteoporosis, serious infection, thrombotic stroke, and death
NSAIDs
Aspirin and celecoxib	Gastrointestinal reaction, renal injury, hepatotoxicity, respiratory tract inflammation, and infection
csDMARDs
Methotrexate	Hepatotoxicity, nephrotoxicity, and carcinogenicity
Sulfasalazine	Hepatitis, thrombocytopenia, proteinuria, and drug-induced lupus erythematosus
Leflunomide	Urticaria, oral ulcers, leukocytopenia, interstitial lung disease, and hypertension
bDMARDs
Etanercept	Cellulitis, increase in liver enzymes, thrombocytopenia, pneumonia, urogenital tract infection, and demyelination
Tocilizumab	Hyperlipidaemia, neutropenia, and hypersensitivity reaction
Rituximab	Hypersensitivity reactions, dyspepsia, pancytopenia, bronchial spasms, and temporary hyperuricemia
Abatacept	Rash, hyperlipidaemia, leukopenia, bronchitis, urogenital tract infection, and headaches

Drug	Target/mechanism	Clinical trial	Disease setting
Non-selective HIF inhibitors
Topotecan	Inhibit transcription and translation activity	FDA	Small cell lung carcinoma
Doxorubicin	Inhibit DNA binding	FDA	Breast cancer
2-Methoxyestradio	Inhibit nuclear translocation and transcription activity	Ⅰ-Ⅱ	Breast cancer and ovarian cancer
HIF-1α inhibitors
Echinomycin	Inhibit DNA binding	Ⅰ-Ⅱ	Solid tumors
EZN-2968	Inhibit mRNA expression	Ⅰ	Advanced solid cancers
Chetomin	Disrupt binding to p300	(-)	Prostate xenografts
HIF-2α inhibitors
PT2385	Inhibit heterodimerization	Ⅰ	Renal cell carcinoma
PT2399	Inhibit heterodimerization	(-)	Renal cell carcinoma
VEGF/VEGFR inhibitors
Bevacizumab	VEGF-A	FDA	Glioblastoma
Apatinib	VEGFR-2	NMPA	Gastric carcinoma
Sunitinib	VEGFR-1/2 and PDGFR-α/β	FDA	Gastrointestinal stromal tumor
Sorafenib	VEGFR-2 and PDGFR-β	FDA	Advanced hepatocellular carcinoma
Cabozantinib	VEGFR-2 and Tie-2	FDA	Metastatic medullary thyroid cancer
Ang-2 inhibitors
MEDI3617	Ang-2	Ⅰ	Advanced solid tumors
LY-3127804	Ang-2	Ⅱ	Metastatic solid tumors
Faricimab	VEGF-A and Ang-2	Ⅲ	Diabetic macular edema

Drug	Target/mechanism	Clinical trial	Disease setting
Non-selective HIF inhibitors
Topotecan	Inhibit transcription and translation activity	FDA	Small cell lung carcinoma
Doxorubicin	Inhibit DNA binding	FDA	Breast cancer
2-Methoxyestradio	Inhibit nuclear translocation and transcription activity	Ⅰ-Ⅱ	Breast cancer and ovarian cancer
HIF-1α inhibitors
Echinomycin	Inhibit DNA binding	Ⅰ-Ⅱ	Solid tumors
EZN-2968	Inhibit mRNA expression	Ⅰ	Advanced solid cancers
Chetomin	Disrupt binding to p300	(-)	Prostate xenografts
HIF-2α inhibitors
PT2385	Inhibit heterodimerization	Ⅰ	Renal cell carcinoma
PT2399	Inhibit heterodimerization	(-)	Renal cell carcinoma
VEGF/VEGFR inhibitors
Bevacizumab	VEGF-A	FDA	Glioblastoma
Apatinib	VEGFR-2	NMPA	Gastric carcinoma
Sunitinib	VEGFR-1/2 and PDGFR-α/β	FDA	Gastrointestinal stromal tumor
Sorafenib	VEGFR-2 and PDGFR-β	FDA	Advanced hepatocellular carcinoma
Cabozantinib	VEGFR-2 and Tie-2	FDA	Metastatic medullary thyroid cancer
Ang-2 inhibitors
MEDI3617	Ang-2	Ⅰ	Advanced solid tumors
LY-3127804	Ang-2	Ⅱ	Metastatic solid tumors
Faricimab	VEGF-A and Ang-2	Ⅲ	Diabetic macular edema

HIF-VEGF-Ang-2信号转导介导的滑膜血管新生在类风湿关节炎中的作用

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甘珮荣 ¹ , 刘超 ² , 吴虹 ¹^,^* , 董心同 ¹ , 柯江涛 ¹ , 陈芳园 ¹

药学学报 | 综述 2021,56(5): 1246-1252

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药学学报 | 综述 2021, 56(5): 1246-1252

HIF-VEGF-Ang-2信号转导介导的滑膜血管新生在类风湿关节炎中的作用

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甘珮荣¹, 刘超², 吴虹¹^,^*, 董心同¹, 柯江涛¹, 陈芳园¹

作者信息

1.安徽中医药大学药学院, 新安医学教育部重点实验室, 中药研究与开发安徽省重点实验室, 安徽合肥 230012

2.安徽医科大学基础医学院, 安徽合肥 230032

通讯作者:

*吴虹, Tel: 13485606565, E-mail: wuhongprof@aliyun.com

The role of HIF-VEGF-Ang-2 signal transduction-mediated synovial angiogenesis in rheumatoid arthritis

Pei-rong GAN¹, Chao LIU², Hong WU¹^,^*, Xin-tong DONG¹, Jiang-tao KE¹, Fang-yuan CHEN¹

Affiliations

1. Anhui Province Key Laboratory of Research and Development of Chinese Medicine, Key Lab of Xin'an Medicine, Ministry of Education, School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China

2. School of Basic Medicine, Anhui Medical University, Hefei 230032, China

出版时间: 2021-05-12 doi: 10.16438/j.0513-4870.2021-0238

文章导航

摘要

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类风湿关节炎（rheumatoid arthritis，RA）是一种以血管新生、炎性因子浸润和关节破坏为主要病理特征的自身免疫性疾病。血管新生推动RA的发展，在其发病机制中发挥重要作用。HIF（hypoxia-inducible factor）-VEGF（vascular endothelial growth factor）-Ang-2（angiopoietin-2）信号转导是诱导滑膜血管新生的关键途径。靶向HIF-VEGF-Ang-2信号转导抑制滑膜血管新生是一种有前景的RA治疗方法。本文对HIF-VEGF-Ang-2信号转导介导的滑膜血管新生在RA中的作用和机制进行综述，以期为RA的治疗提供新的靶点和策略。

关键词

类风湿关节炎 / 血管新生 / 缺氧诱导因子 / 血管内皮生长因子 / 血管生成素-2

Abstract

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Rheumatoid arthritis (RA) is an autoimmune disease with angiogenesis, inflammatory factor infiltration and joint destruction as the main pathological features. Angiogenesis promotes the development of RA and plays an important role in its pathogenesis. The hypoxia-inducible factor (HIF)-vascular endothelial growth factor (VEGF)-angiopoietin-2 (Ang-2) signal transduction is a critical pathway to induce synovial angiogenesis. Targeting HIF-VEGF-Ang-2 signal transduction to inhibit synovial angiogenesis is a promising approach for RA treatment. This article reviews the role and mechanism of HIF-VEGF-Ang-2 signal transduction-mediated synovial angiogenesis in RA, in order to provide a new target and strategy for RA treatment.

Key words

rheumatoid arthritis / angiogenesis / hypoxia-inducible factor / vascular endothelial growth factor / angiopoietin-2

引用本文

甘珮荣, 刘超, 吴虹, 董心同, 柯江涛, 陈芳园. HIF-VEGF-Ang-2信号转导介导的滑膜血管新生在类风湿关节炎中的作用. 药学学报, 2021 , 56 (5) : 1246 -1252 . DOI: 10.16438/j.0513-4870.2021-0238

Pei-rong GAN, Chao LIU, Hong WU, Xin-tong DONG, Jiang-tao KE, Fang-yuan CHEN. The role of HIF-VEGF-Ang-2 signal transduction-mediated synovial angiogenesis in rheumatoid arthritis[J]. Acta Pharmaceutica Sinica, 2021 , 56 (5) : 1246 -1252 . DOI: 10.16438/j.0513-4870.2021-0238

正文

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类风湿关节炎(rheumatoid arthritis, RA) 是一种慢性炎症性自身免疫性疾病, 其基本病理特征是血管新生、关节滑膜炎、滑膜组织增生、血管翳形成, 以及关节软骨和骨的破坏^[1]。血管新生为炎症部位输送炎性细胞和炎性因子, 维持RA慢性炎症状态; 促进血管翳形成和发展, 导致关节软骨的侵蚀和破坏。抑制滑膜血管新生可减轻滑膜炎症, 抑制血管翳形成, 从而缓解RA病情。RA中大量滑膜细胞增殖, 使得对氧的需求增加, 造成滑膜局部缺氧。在这种缺氧微环境中, 缺氧诱导因子(hypoxia-inducible factor, HIF) 水平升高(尤其是HIF-1α), 激活下游靶基因转录, 如血管内皮生长因子(vascular endothelial growth factor, VEGF)。VEGF可诱导内皮细胞中的怀布尔-帕拉德体(Weibel-Palade body, WPB) 释放血管生成素-2 (angiopoietin-2, Ang-2), 协同促进血管新生。本文通过在PubMed和中国知网数据库检索“HIF”、“VEGF”、“Ang-2”、“血管新生”和“RA”等关键词并梳理相关文献, 阐述HIF-VEGF-Ang-2信号转导介导的滑膜血管新生对RA的作用及其机制, 以期通过靶向HIF-VEGF-Ang-2信号转导, 抑制滑膜血管新生, 为RA治疗提供新思路。

1 血管新生

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血管新生是指在已有血管基础上形成新毛细血管的过程, 该过程受多种分子调控。正常情况下的促血管生成因子与抑血管生成因子处于动态平衡, 当受到某些因素刺激时, 促血管生成因子占优势, 促进血管新生。生理性血管新生在胚胎形成和创面愈合中发挥关键作用, 而病理性血管新生则会加快某些疾病的发展, 如RA和肿瘤等。RA关节滑膜内皮衬里细胞释放基质金属蛋白酶(matrix metalloproteinases, MMPs), 降解内皮细胞基底膜, 使周细胞脱落, 内皮细胞向血管周围基质迁移, 并增殖和黏附形成管腔。管腔交汇形成血管袢, 经基质重构、周细胞和血管平滑肌细胞缠绕及血管吻合形成血管网^[2]。有研究发现, 与骨关节炎患者相比, RA患者滑膜组织中MMP14、VEGF和血管生成标记物CD31表达显著增加^[3]。促血管生成因子如生长因子(VEGF、HIF和Ang)、MMPs、趋化因子以及促炎细胞因子在滑膜血管新生中直接或间接地发挥作用。其中, HIF、VEGF和Ang-2组成的信号转导在滑膜血管新生中发挥关键作用。

2 HIF-VEGF-Ang-2信号转导

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2.1 HIF

缺氧诱导因子(HIF) 是调节细胞对氧环境改变适应性的异源二聚体核转录因子, 由氧依赖性的α亚基和细胞核中组成性表达的β亚基构成^[4]。HIF-α分为HIF-1α、HIF-2α和HIF-3α。HIF-1α和HIF-2α结构相似(图 1), 均含有碱性螺旋-环-螺旋(basic helix loop helix, bHLH) 结构域、PAS (PER-ARNT-SIM) 结构域、反式激活结构域(transactivation domains, N-TAD, C-TAD) 以及氧依赖性降解结构域(oxygen-dependent degradation domain, ODDD)。其中, bHLH结构域可与缺氧反应元件(hypoxia response element, HRE) 结合, PAS结构域是HIF-α与HIF-β结合形成二聚体的部位, C-TAD与转录共激活因子p300/CBP结合[CBP: 环腺苷酸效应元件结合蛋白结合蛋白(cyclic adenosine monophosphate response element binding protein binding protein)], 激活缺氧相关基因转录。HIF-3α也含有类似结构(图 1), 但其缺乏C-TAD, 不具有激活靶基因转录的活性^[5]。HIF-1α在所有组织中表达, 是最主要的氧调节因子, 而HIF-2α的表达具有组织选择性。

2019年诺贝尔生理学或医学奖获得者美国医学家威廉·凯林(William G. Kaelin Jr.)、格雷格·塞门扎(Gregg L. Semenza) 和英国细胞和分子生物学家彼得·拉特克利夫(Peter J. Ratcliffe) 提出细胞感知和适应氧气的机制, 揭示细胞可以通过希佩尔-林道病肿瘤抑制基因(von Hippel-Lindau, VHL)/HIF信号通路适应氧环境变化。VHL位于人类第3号染色体短臂上, 表达肿瘤抑制蛋白(protein von Hippel-Lindau, pVHL), 该蛋白是E3泛素连接酶复合物的识别底物, 介导HIF-α泛素化, 使HIF-α被蛋白酶体降解。HIF-α脯氨酸残基羟基化调节VHL对HIF-α的降解作用, 这一羟基化过程由脯氨酸羟化酶(prolyl hydroxylase domains, PHDs) 完成。PHD是一种氧依赖性双加氧酶, 主要有PHD1、PHD2、PHD3和PHD4。HIF-1α和HIF-2α脯氨酸残基的羟基化分别由PHD2和PHD3完成^[5]。

HIF-1α的表达受多种信号通路调控, 如氧依赖性通路PHDs/HIF-1α/pVHL, 以及非氧依赖性通路核因子κB、c-Jun氨基末端激酶/信号转导及转录激活蛋白和磷脂酰肌醇3-激酶/蛋白激酶B等^[6]。在这些信号通路中, PHDs/HIF-1α/pVHL信号通路发挥主要作用。常氧条件下, HIF-1α的ODDD中脯氨酸残基(Pro402和Pro564) 被PHD2羟基化, 然后被pVHL识别, 经泛素-蛋白酶体途径降解。此外, HIF-1抑制因子(factor-inhibiting HIF-1, FIH-1) 羟基化HIF-1α的C-TAD中的天冬酰胺残基(Asn803), 阻止其与p300/CBP结合, 从而抑制HIF-1α激活缺氧相关基因转录的活性。低氧条件下, PHD2和FIH-1羟化作用受抑制, pVHL不能识别HIF-1α, 导致HIF-1α降解减少并在细胞质中积累, 然后转移至细胞核中与HIF-1β二聚化, HIF-1异源二聚体被p300/CBP识别, 并与靶基因启动子上游的HRE结合, 启动该基因的转录^[4]。

RA关节中大量滑膜细胞增殖引起的缺氧导致HIF-1α在胞质中积聚, 并移位至细胞核与HIF-1β和p300/CBP结合, 最终诱导巨噬细胞样和成纤维细胞样滑膜细胞表达VEGF、肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)、白细胞介素-6 (interleukin-6, IL-6)、IL-8以及基质金属蛋白酶(MMP-1、MMP-3和MMP-13)^[7], 从而诱导滑膜血管新生, 加重滑膜炎症和关节软骨的破坏。HIF-2α的表达也受氧依赖性途径PHDs/HIF-2α/pVHL的调控。低氧条件下, HIF-2α激活下游靶基因VEGF转录, 促进血管新生^[8]。

2.2 VEGF

VEGF是一种非常重要的促血管生成因子, 可作为血管内皮细胞的特异性有丝分裂原, 促进内皮细胞增殖和迁移, 同时还可以促进间质胶原酶分泌, 降解细胞基质, 在血管新生中发挥核心作用。VEGF家族包括VEGF-A、VEGF-B、VEGF-C、VEGF-D、VEGF-E、VEGF-F以及胎盘生长因子, 其中VEGF-A是最有效的促血管生成因子。血管内皮生长因子受体(vascular endothelial growth factor receptors, VEGFRs) 有酪氨酸激酶受体VEGFR-1、VEGFR-2和VEGFR-3, 以及非酪氨酸激酶受体如神经纤维网蛋白^[9], 酪氨酸激酶受体是VEGF最主要的功能受体。VEGFR-1和VEGFR-2主要分布在血管内皮表面, 调节血管新生。VEGFR-3主要分布在淋巴内皮表面, 调节淋巴管生成。VEGF-A与VEGFR-1结合的亲和力高, 但VEGFR-1的酪氨酸激酶活性低于VEGFR-2, 故VEGFR-2是VEGF最重要的受体。

VEGF与滑膜血管内皮上的受体结合, 促进滑膜血管新生, 增加血管通透性和炎性因子的释放。在RA患者的血清中, VEGF水平较高, 并与滑膜炎严重程度和疾病活动性密切相关^[10]。Li等^[11]采用胶原诱导的关节炎(collagen-induced arthritis, CIA) 小鼠模型研究芹菜素对RA的治疗作用, 发现芹菜素可显著降低CIA小鼠滑膜组织中VEGF、VEGFR-1和VEGFR-2的蛋白表达水平, 从而抑制滑膜血管新生, 发挥对RA的治疗作用。

2.3 Ang

Ang分为Ang-1、Ang-2、Ang-3和Ang-4。其中Ang-1和Ang-2在血管新生中发挥重要作用。酪氨酸激酶受体-2 (tyrosine kinase receptors with immunoglobulin and EGF homology domains-2, Tie-2) 为Ang的特异性受体, 主要由血管内皮细胞分泌。现有研究发现, 周细胞可以分泌少量Tie-2, 加强与内皮细胞的连接^[12]。Tie-1为孤儿受体, 目前尚未发现能与其特异性结合的配体。Ang-1主要由周细胞表达, 通过旁分泌方式与内皮细胞上的Tie-2结合, 促进内皮细胞迁移和黏附。此外, Ang-1也可以通过自分泌方式作用于周细胞, 促进周细胞向内皮细胞募集, 包绕新生血管, 促进血管成熟和稳定, 在伤口愈合中发挥重要作用^[13]。

Ang-2由内皮细胞分泌并储存在其特异性细胞器怀布尔-帕拉德体(WPB) 中。WPB是由血管性血友病因子(von Willebrand factor, vWF) 聚合形成的杆状细胞器, 在TNF、缺氧和VEGF等刺激下, WPB会迅速释放Ang-2^[14]。Ang-2竞争性结合Tie-2, 抑制Ang-1作用。在非炎症环境中, Ang-2可作为Tie-2的弱激动剂; 而在炎症环境中, Ang-2主要起拮抗作用^[14]。在RA患者滑膜组织中, Ang-2高表达^[15], 抑制周细胞中Ang-1/Tie-2自分泌信号, 促进周细胞脱离血管内皮细胞, 使得内皮细胞去稳定, 这是内皮细胞出芽、迁移的关键步骤。裸露的血管内皮细胞在VEGF诱导下出芽、迁移并逐渐形成新的血管; VEGF不存在时, 原有血管则会退化。缺乏周细胞覆盖的血管不成熟, 结构和功能不完整, 通透性增大^[16]。Ang-2在肿瘤血管内皮细胞中高表达, 诱导紊乱、渗漏的肿瘤微血管形成, 促进肿瘤细胞的侵袭和转移^[17]。Kayakabe等^[18]发现, IL-6上调VEGF和Ang-2的表达, 下调Ang-1的表达, 诱导滑膜形成不稳定和不成熟的微血管。

2.4 HIF-VEGF-Ang-2

在RA滑膜缺氧微环境中, PHDs和FIH活性降低, HIF-1α和HIF-2α在胞质中降解受阻, 大量积聚, 并移位至细胞核中分别与HIF-1β和HIF-2β结合形成异源二聚体, 与p300/CBP相互作用形成复合物, 然后结合VEGF启动子上游核心序列为5'-A/GCGTG-3'的HRE, 形成转录起始复合物, 启动VEGF的转录, 使得滑膜巨噬细胞和成纤维细胞VEGF表达增加。VEGF与VEGFR, 尤其是VEGFR-2结合后, 刺激内皮细胞中的WPB释放Ang-2。Ang-2竞争性地结合Tie-2, 抑制Ang-1自分泌作用, 使嵌入血管内皮细胞表层基底膜中的周细胞脱落, 解除周细胞与内皮细胞连接。VEGF诱导活化的内皮细胞出芽, 启动血管新生(图 2)。

Forsythe等^[19]于1996年研究发现, HIF-1α可以与VEGF上的HRE结合, 激活VEGF转录。随后, Carroll等^[20]发现, HIF-2α可以激活肾癌细胞中VEGF的转录。这表明VEGF是HIF-1α和HIF-2α共同的靶基因。Ryu等^[21]在CIA小鼠和RA患者滑膜组织中检测到HIF-1α和HIF-2α高表达。构建短发卡RNA (short hairpin RNA, shRNA) 慢病毒表达载体, 转染CIA大鼠滑膜细胞干扰HIF-1α, 可以显著降低VEGF的蛋白表达水平, 并减少滑膜新生血管数量^[22]。目前的研究证实, HIF/VEGF信号途径可以促进滑膜血管新生^[23]。有研究发现, VEGF与内皮细胞上的VEGFR-2结合可以诱导人脐静脉内皮细胞中的WPB释放vWF和Ang-2^[24]。与正常大鼠相比, CIA大鼠滑膜组织中VEGF的mRNA水平和Ang-2蛋白表达水平明显升高^[25]。Jiang等^[26]研究表明, 外源性VEGF可以显著增加离体RA患者滑膜组织中Ang-2蛋白表达, 并发现IL-35可通过抑制VEGF/Ang-2信号途径, 抑制RA滑膜血管新生。

3 滑膜血管新生在类风湿关节炎中的作用

收起

RA初期, 滑膜衬里层的巨噬细胞样和成纤维细胞样滑膜细胞大量增殖。同时, 滑膜下层被CD4⁺ T细胞、B细胞和巨噬细胞浸润^[27]。滑膜细胞过度增殖以及炎症细胞迁移, 使得滑膜对氧的需求增加; 此外, 滑膜增生导致滑膜细胞与邻近血管的距离增加, 超过氧的扩散范围, 使得氧供不足; 同时, 滑膜液运动和积聚破坏滑膜的血管系统, 导致血供不足, 从而加剧缺氧^[28]。HIF-α响应缺氧, 刺激巨噬细胞样和成纤维细胞样滑膜细胞表达大量的VEGF, VEGF诱导内皮细胞中的WPB释放Ang-2, HIF-VEGF-Ang-2信号转导被激活, 诱导滑膜血管新生, 改善滑膜组织缺氧, 但由于新生血管的结构和功能异常, RA滑膜仍维持缺氧状态。RA后期主要表现为大量微血管形成。新生微血管向炎性滑膜输送炎症细胞, 促进炎性因子释放, 加重RA滑膜炎症。同时, 新生血管、炎症细胞和滑膜细胞共同构成血管翳, 侵蚀、破坏关节软骨和骨, 导致关节变薄, 发黏和破裂, 严重时导致关节功能丧失^[27]。

RA滑膜新生血管的数量与滑膜增生、关节肿胀和关节破坏程度密切相关。抑制滑膜血管新生, 可以有效治疗RA。Xu等^[29]建立CIA小鼠模型, 采用免疫组织化学法和酶联免疫吸附法检测VEGF和HIF-1α水平, 进行关节炎指数评分、组织病理学评分和滑膜微血管密度(microvessel density, MVD) 分析, 探究紫杉醇对RA的治疗作用及其机制, 发现紫杉醇可通过下调HIF-1α和VEGF水平, 抑制滑膜血管新生, 从而降低CIA小鼠的关节炎指数评分和MVD, 并改善其关节骨的破坏。

4 靶向HIF-VEGF-Ang-2信号转导

收起

目前, 治疗RA的药物主要有糖皮质激素、非甾体抗炎药(nonsteroidal antiinflammatory drugs, NSAIDs)、传统合成病情缓解抗风湿药物(conventional synthetic disease-modifying antirheumatic drugs, csDMARDs) 和生物病情缓解抗风湿药物(biologic disease-modifying antirheumatic drugs, bDMARDs)。糖皮质激素不良反应较多, 仅在短期内低剂量联合DMARDs用于RA患者早期治疗。NSAIDs的作用主要是减轻炎症, 缓解疼痛, 但不能抑制关节破坏。甲氨蝶呤(methotrexate, MTX) 是一线csDMARDs, 可单用或与其他DMARDs联合使用, 其治疗RA存在剂量依赖性反应, 高剂量MTX容易产生肝毒性、肾毒性和致癌等不良反应^[30]。与csDMARDs相比, bDMARDs作用更明确, 针对性更强, 但长期使用这些药物会影响免疫功能, 增加感染风险^[31]。现有治疗RA的药物存在一些毒副作用(表 1)^{[32, 33]}, 因此, 急需寻找高效、低毒的RA治疗药物。

血管新生抑制疗法已经广泛应用于肿瘤治疗。靶向HIF-VEGF-Ang-2信号转导, 抑制滑膜血管新生, 可以有效缓解RA病情。目前, HIF抑制剂的研发思路主要是抑制HIF-α的mRNA水平和蛋白表达水平, 促进HIF-α降解, 抑制HIF-α和HIF-β的二聚化, 阻断HIF-α/p300蛋白-蛋白相互作用, 以及抑制HIF-α与靶基因结合等。非选择性HIF抑制剂有拓扑替康(topotecan)、多柔比星(doxorubicin) 和2-甲氧基雌二醇(2-methoxyestradio)。拓扑替康是美国批准用于治疗小细胞肺癌的二线化疗药物, 它可以在转录和翻译水平上抑制HIF-α, 并抑制VEGF的生成^[34]。多柔比星用于乳腺癌的临床治疗, 可以阻断HIF-1α和HIF-2α与靶基因的结合^{[35, 36]}。HIF-1α选择性抑制剂有棘霉素(echinomycin)、EZN-2968和壳聚糖(chetomin), 均未用于临床。棘霉素与VEGF上的HRE结合, 竞争性抑制HIF-1α与VEGF的结合^[37], 已进入治疗实体瘤的Ⅱ期临床试验, 但由于其对难治性实体瘤未显示疗效, 被暂停研究。最近有研究发现, 将棘霉素制成纳米脂质体制剂可以有效抑制实体瘤生长和转移^[38]。HIF-2α抑制剂有PT2385和PT2399, 均可抑制HIF-2α二聚化。

靶向VEGF/VEGFR信号通路的抗血管新生药物在临床上应用较多, 主要有单克隆抗体贝伐单抗(bevacizumab)、阿帕替尼(apatinib), 以及小分子多激酶抑制剂舒尼替尼(sunitinib)、索拉非尼(sorafenib) 和卡博替尼(cabozantinib)。贝伐单抗是第一个成功上市的抗肿瘤血管新生药物, 它可与VEGF-A选择性结合, 阻止VEGF-A与VEGFR结合^[39]。阿帕替尼是我国自主研发的抗血管新生药物, 它通过与VEGFR-2结合, 抑制VEGF与VEGFR-2结合, 用于晚期胃癌治疗^[40]。

目前, 靶向Ang-2的药物处于临床或临床前研究阶段。MEDI3617是抗Ang-2的单克隆抗体, 已进入治疗晚期实体瘤的Ⅰ期临床试验阶段。近期研究表明, MEDI3617治疗卵巢癌会出现严重水肿反应, 已终止研究^[41]。LY-3127804作为抗Ang-2的单克隆抗体, 处于治疗晚期和转移性实体瘤的Ⅱ期临床试验阶段^[42]。Faricimab是靶向VEGF-A和Ang-2的双特异性抗体, 处于治疗糖尿病性黄斑水肿的Ⅲ期临床试验阶段^[43]。靶向HIF-VEGF-Ang-2信号转导药物的靶点或机制、临床试验阶段和治疗类型见表 2。

5 展望

收起

HIF-VEGF-Ang-2信号转导在滑膜血管新生中发挥关键作用, 靶向该信号转导, 抑制滑膜血管新生, 缓解RA病情, 为RA治疗提供新靶点。同时, 需要注意地是, 血管新生是多分子、多信号通路参与调控的复杂过程。因此, 探讨更多的信号通路在滑膜血管新生中的作用机制, 靶向多个信号通路, 可以更好地发挥抗血管新生作用, 更加有效地治疗RA。

作者贡献: 甘珮荣负责文章撰写及图表绘制; 刘超和吴虹提供文章的方向和思路; 董心同负责文献查找; 柯江涛和陈芳园负责语句修改和文章润色。

利益冲突: 所有作者均声明不存在利益冲突。

基金

收起

国家科学自然基金资助项目(81874360)
国家科学自然基金资助项目(81473400)
国家科学自然基金资助项目(81073122)

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2021年第56卷第5期

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doi: 10.16438/j.0513-4870.2021-0238

接收时间：2021-02-19
首发时间：2025-12-18
出版时间：2021-05-12

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收稿日期：2021-02-19
修回日期：2021-03-22

基金

国家科学自然基金资助项目(81874360)

国家科学自然基金资助项目(81473400)

国家科学自然基金资助项目(81073122)

作者信息

1.安徽中医药大学药学院, 新安医学教育部重点实验室, 中药研究与开发安徽省重点实验室, 安徽合肥 230012

2.安徽医科大学基础医学院, 安徽合肥 230032

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*吴虹, Tel: 13485606565, E-mail: wuhongprof@aliyun.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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TxT

Drug	Side effect
Glucocorticoid	Diabetes, osteoporosis, serious infection, thrombotic stroke, and death
NSAIDs
Aspirin and celecoxib	Gastrointestinal reaction, renal injury, hepatotoxicity, respiratory tract inflammation, and infection
csDMARDs
Methotrexate	Hepatotoxicity, nephrotoxicity, and carcinogenicity
Sulfasalazine	Hepatitis, thrombocytopenia, proteinuria, and drug-induced lupus erythematosus
Leflunomide	Urticaria, oral ulcers, leukocytopenia, interstitial lung disease, and hypertension
bDMARDs
Etanercept	Cellulitis, increase in liver enzymes, thrombocytopenia, pneumonia, urogenital tract infection, and demyelination
Tocilizumab	Hyperlipidaemia, neutropenia, and hypersensitivity reaction
Rituximab	Hypersensitivity reactions, dyspepsia, pancytopenia, bronchial spasms, and temporary hyperuricemia
Abatacept	Rash, hyperlipidaemia, leukopenia, bronchitis, urogenital tract infection, and headaches

Drug

Side effect

Glucocorticoid

Diabetes, osteoporosis, serious infection, thrombotic stroke, and death

NSAIDs

Aspirin and
celecoxib

Gastrointestinal reaction, renal injury, hepatotoxicity, respiratory tract inflammation, and infection

csDMARDs

Methotrexate

Hepatotoxicity, nephrotoxicity, and carcinogenicity

Sulfasalazine

Hepatitis, thrombocytopenia, proteinuria, and drug-induced lupus erythematosus

Leflunomide

Urticaria, oral ulcers, leukocytopenia, interstitial lung disease, and hypertension

bDMARDs

Etanercept

Cellulitis, increase in liver enzymes, thrombocytopenia, pneumonia, urogenital tract infection, and demyelination

Tocilizumab

Hyperlipidaemia, neutropenia, and hypersensitivity reaction

Rituximab

Hypersensitivity reactions, dyspepsia, pancytopenia, bronchial spasms, and temporary hyperuricemia

Abatacept

Rash, hyperlipidaemia, leukopenia, bronchitis, urogenital tract infection, and headaches

Drug	Target/mechanism	Clinical trial	Disease setting
Non-selective HIF inhibitors
Topotecan	Inhibit transcription and translation activity	FDA	Small cell lung carcinoma
Doxorubicin	Inhibit DNA binding	FDA	Breast cancer
2-Methoxyestradio	Inhibit nuclear translocation and transcription activity	Ⅰ-Ⅱ	Breast cancer and ovarian cancer
HIF-1α inhibitors
Echinomycin	Inhibit DNA binding	Ⅰ-Ⅱ	Solid tumors
EZN-2968	Inhibit mRNA expression	Ⅰ	Advanced solid cancers
Chetomin	Disrupt binding to p300	(-)	Prostate xenografts
HIF-2α inhibitors
PT2385	Inhibit heterodimerization	Ⅰ	Renal cell carcinoma
PT2399	Inhibit heterodimerization	(-)	Renal cell carcinoma
VEGF/VEGFR inhibitors
Bevacizumab	VEGF-A	FDA	Glioblastoma
Apatinib	VEGFR-2	NMPA	Gastric carcinoma
Sunitinib	VEGFR-1/2 and PDGFR-α/β	FDA	Gastrointestinal stromal tumor
Sorafenib	VEGFR-2 and PDGFR-β	FDA	Advanced hepatocellular carcinoma
Cabozantinib	VEGFR-2 and Tie-2	FDA	Metastatic medullary thyroid cancer
Ang-2 inhibitors
MEDI3617	Ang-2	Ⅰ	Advanced solid tumors
LY-3127804	Ang-2	Ⅱ	Metastatic solid tumors
Faricimab	VEGF-A and Ang-2	Ⅲ	Diabetic macular edema

Drug

Target/mechanism

Clinical trial

Disease setting

Non-selective HIF inhibitors

Topotecan

Inhibit transcription and translation activity

FDA

Small cell lung carcinoma

Doxorubicin

Inhibit DNA binding

FDA

Breast cancer

2-Methoxyestradio

Inhibit nuclear translocation and transcription activity

Ⅰ-Ⅱ

Breast cancer and ovarian cancer

HIF-1α inhibitors

Echinomycin

Inhibit DNA binding

Ⅰ-Ⅱ

Solid tumors

EZN-2968

Inhibit mRNA expression

Ⅰ

Advanced solid cancers

Chetomin

Disrupt binding to p300

(-)

Prostate xenografts

HIF-2α inhibitors

PT2385

Inhibit heterodimerization

Ⅰ

Renal cell carcinoma

PT2399

Inhibit heterodimerization

(-)

Renal cell carcinoma

VEGF/VEGFR inhibitors

Bevacizumab

VEGF-A

FDA

Glioblastoma

Apatinib

VEGFR-2

NMPA

Gastric carcinoma

Sunitinib

VEGFR-1/2 and PDGFR-α/β

FDA

Gastrointestinal stromal tumor

Sorafenib

VEGFR-2 and PDGFR-β

FDA

Advanced hepatocellular carcinoma

Cabozantinib

VEGFR-2 and Tie-2

FDA

Metastatic medullary thyroid cancer

Ang-2 inhibitors

MEDI3617

Ang-2

Ⅰ

Advanced solid tumors

LY-3127804

Ang-2

Ⅱ

Metastatic solid tumors

Faricimab

VEGF-A and Ang-2

Ⅲ

Diabetic macular edema