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浙江大学学报（医学版）
浙江大学学报（医学版）  2018, Vol. 47 Issue (2): 207-212    DOI: 10.3785/j.issn.1008-9292.2018.04.16
综述     
自噬在肺动脉高压发生和发展中的调节作用
吕丹丹(),应可净*()
浙江大学医学院附属邵逸夫医院呼吸内科, 浙江 杭州 310016
Regulatory role of autophagy in development of pulmonary artery hypertension
LYU Dandan(),YING Kejing*()
Department of Respiratory Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
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摘要：

肺动脉高压是一类多病因导致肺血管重构、肺动脉阻力进行性增高的慢性疾病，其发病机制错综复杂。近年研究发现，自噬作为真核生物维持细胞内环境稳定的一种自我保护机制，参与多种类型肺动脉高压的发生和发展。自噬通过调节肺血管壁细胞的生存、凋亡以及血管活性物质和炎症介质分泌等病理变化影响肺血管稳态。一些能调节自噬活性的药物对肺动脉高压的治疗有很好的临床应用价值。本文综述了自噬在肺动脉高压发生和发展中的调节作用，为临床治疗提供新的思路。
关键词： 高血压, 肺性/病理学;  自噬/生理学;  肺动脉/病理学;  内皮, 血管/药物作用;  综述    
Abstract:

Pulmonary arterial hypertension (PAH) is a multi-etiological chronic disease characterized by a progressive elevation in pulmonary resistance and vascular remodeling. Its pathogenesis is complicated. Recently, emerging researches suggest that autophagy, as a self-protection mechanism maintaining the intracellular environment homeostasis in eukaryotes, participate in the occurrence and development of various types of PAH. Autophagy can regulate the survival, apoptosis of pulmonary vascular wall cells and secretion of vasoactive substances and inflammatory cytokines, thus influencing pulmonary vascular homeostasis. Some drugs based on regulating autophagy activity can effectively improve the prognosis of PAH. In this article, the regulatory role of autophagy on the development of pulmonary hypertension is reviewed to provide insight into PAH and its treatment.
Key words: Hypertension, pulmonary/pathology    Autophagy/physiology    Pulmonary artery/pathology    Endothelium, vascular/drug effects    Review
收稿日期: 2018-01-07 出版日期: 2018-07-24
:  R543.2  
基金资助: 国家自然科学基金(81270107);浙江省医药卫生科技计划(2016KYB149)
通讯作者: 应可净     E-mail: 21618303@zju.edu.cn;3197061@zju.edu.cn
作者简介: 吕丹丹(1991-), 女, 硕士研究生, 主要从事肺动脉高压、肺纤维化的基础研究; E-mail:21618303@zju.edu.cn; https://orcid.org/0000-0003-1879-6257
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引用本文:

吕丹丹,应可净. 自噬在肺动脉高压发生和发展中的调节作用[J]. 浙江大学学报（医学版）, 2018, 47(2): 207-212.

LYU Dandan,YING Kejing. Regulatory role of autophagy in development of pulmonary artery hypertension. J Zhejiang Univ (Med Sci), 2018, 47(2): 207-212.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2018.04.16    或    http://www.zjujournals.com/med/CN/Y2018/V47/I2/207

1 PESTO S , BEGIC Z , PREVLJAK S et al. Pulmonary hypertension-new trends of diagnostic and therapy[J]. Med Arch, 2016, 70 (4): 303- 307
doi: 10.5455/medarh.
2 HUBER L C , BYE H , BROCK M . The pathogenesis of pulmonary hypertension-an update[J]. Swiss Med Wkly, 2015, 145 w14202
3 KUWANO K , ARAYA J , HARA H et al. Cellular senescence and autophagy in the pathogenesis of chronic obstructive pulmonary disease(COPD) and idiopathic pulmonary fibrosis(IPF)[J]. Respir Investig, 2016, 54 (6): 397- 406
doi: 10.1016/j.resinv.2016.03.010
4 MIZUMURA K , CLOONAN S , CHOI M E et al. Autophagy:friend or foe in lung disease?[J]. Ann Am Thorac Soc, 2016, 13 (Suppl 1): S40- S47
5 ABADA A , ELAZAR Z . Getting ready for building:signaling and autophagosome biogenesis[J]. EMBO Rep, 2014, 15 (8): 839- 852
doi: 10.15252/embr.201439076
6 KIM Y C , GUAN K L . mTOR:a pharmacologic target for autophagy regulation[J]. J Clin Invest, 2015, 125 (1): 25- 32
doi: 10.1172/JCI73939
7 PAN C C , KUMAR S , SHAH N et al. Endoglin regulation of Smad2 function mediates Beclin1 expression and endothelial autophagy[J]. J Biol Chem, 2015, 290 (24): 14884- 14892
doi: 10.1074/jbc.M114.630178
8 THIYAGARAJAN V , SIVALINGAM K S , VISWANADHA V P et al. 16-hydroxy-cleroda-3, 13-dien-16, 15-olide induced glioma cell autophagy via ROS generation and activation of p38 MAPK and ERK-1/2[J]. Environ Toxicol Pharmacol, 2016, 45 202- 211
doi: 10.1016/j.etap.2016.06.005
9 LIM C J , LEE Y M , KANG S G et al. Aquatide activation of SIRT1 reduces cellular senescence through a SIRT1-FOXO1-autophagy axis[J]. Biomol Ther(Seoul), 2017, 25 (5): 511- 518
doi: 10.4062/biomolther.2017.119
10 GUO F , LI X , PENG J et al. Autophagy regulates vascular endothelial cell eNOS and ET-1 expression induced by laminar shear stress in an ex vivo perfused system[J]. Ann Biomed Eng, 2014, 42 (9): 1978- 1988
doi: 10.1007/s10439-014-1033-5
11 BHARATH L P , MUELLER R , LI Y et al. Impairment of autophagy in endothelial cells prevents shear-stress-induced increases in nitric oxide bioavailability[J]. Can J Physiol Pharmacol, 2014, 92 (7): 605- 612
doi: 10.1139/cjpp-2014-0017
12 SHAN H , GUO D , LI X et al. From autophagy to senescence and apoptosis in Angiotensin Ⅱ-treated vascular endothelial cells[J]. APMIS, 2014, 122 (10): 985- 992
doi: 10.1111/apm.2014.122.issue-10
13 CHEN F , CHEN B , XIAO F Q et al. Autophagy protects against senescence and apoptosis via the RAS-mitochondria in high-glucose-induced endothelial cells[J]. Cell Physiol Biochem, 2014, 33 (4): 1058- 1074
doi: 10.1159/000358676
14 SHAPIRO S , TRAIGER G L , TURNER M et al. Sex differences in the diagnosis, treatment, and outcome of patients with pulmonary arterial hypertension enrolled in the registry to evaluate early and long-term pulmonary arterial hypertension disease management[J]. Chest, 2012, 141 (2): 363- 373
doi: 10.1378/chest.10-3114
15 LAHM T , PETRACHE I . LC3 as a potential therapeutic target in hypoxia-induced pulmonary hypertension[J]. Autophagy, 2012, 8 (7): 1146- 1147
doi: 10.4161/auto.20520
16 O'DONNELL E , FLORAS J S , HARVEY P J . Estrogen status and the renin angiotensin aldosterone system[J]. Am J Physiol Regul Integr Comp Physiol, 2014, 307 (5): R498- R500
doi: 10.1152/ajpregu.00182.2014
17 JIANG P , LAN Y , LUO J et al. Rapamycin promoted thrombosis and platelet adhesion to endothelial cells by inducing membrane remodeling[J]. BMC Cell Biol, 2014, 15 7
doi: 10.1186/1471-2121-15-7
18 FENG W , CHANG C , LUO D et al. Dissection of autophagy in human platelets[J]. Autophagy, 2014, 10 (4): 642- 651
doi: 10.4161/auto.27832
19 MAUGERI N , CAMPANA L , GAVINA M et al. Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps[J]. J Thromb Haemost, 2014, 12 (12): 2074- 2088
doi: 10.1111/jth.2014.12.issue-12
20 YAU J W , SINGH K K , HOU Y et al. Endothelial-specific deletion of autophagy-related 7(ATG7) attenuates arterial thrombosis in mice[J]. J Thorac Cardiovasc Surg, 2017, 154 (3): 978- 988
doi: 10.1016/j.jtcvs.2017.02.058
21 FU J , CHEN Y F , ZHAO X et al. Targeted delivery of pulmonary arterial endothelial cells overexpressing interleukin-8 receptors attenuates monocrotaline-induced pulmonary vascular remodeling[J]. Arterioscler Thromb Vasc Biol, 2014, 34 (7): 1539- 1547
doi: 10.1161/ATVBAHA.114.303821
22 YANG M , DENG C , WU D et al. The role of mononuclear cell tissue factor and inflammatory cytokines in patients with chronic thromboembolic pulmonary hypertension[J]. J Thromb Thrombolysis, 2016, 42 (1): 38- 45
doi: 10.1007/s11239-015-1323-2
23 SAITOH T , FUJITA N , JANG M H et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production[J]. Nature, 2008, 456 (7219): 264- 268
doi: 10.1038/nature07383
24 TAL M C , SASAI M , LEE H K et al. Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling[J]. Proc Natl Acad Sci U S A, 2009, 106 (8): 2770- 2775
doi: 10.1073/pnas.0807694106
25 CHEN M L , YI L , JIN X et al. Resveratrol attenuates vascular endothelial inflammation by inducing autophagy through the cAMP signaling pathway[J]. Autophagy, 2013, 9 (12): 2033- 2045
doi: 10.4161/auto.26336
26 HU Y , LOU J , MAO Y Y et al. Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury[J]. Autophagy, 2016, 12 (12): 2286- 2299
doi: 10.1080/15548627.2016.1230584
27 SAKAO S , HAO H , TANABE N et al. Endothelial-like cells in chronic thromboembolic pulmonary hypertension:crosstalk with myofibroblast-like cells[J]. Respir Res, 2011, 12 109
doi: 10.1186/1465-9921-12-109
28 STENMARK K R , FRID M , PERROS F . Endothelial-to-mesenchymal transition:an evolving paradigm and a promising therapeutic target in PAH[J]. Circulation, 2016, 133 (18): 1734- 1737
doi: 10.1161/CIRCULATIONAHA.116.022479
29 TARASEVICIENE-STEWART L , KASAHARA Y , ALGER L et al. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension[J]. FASEB J, 2001, 15 (2): 427- 438
doi: 10.1096/fj.00-0343com
30 YANG J , YAO S . JNK-Bcl-2/Bcl-xL-Bax/Bak pathway mediates the crosstalk between matrine-induced autophagy and apoptosis via interplay with Beclin 1[J]. Int J Mol Sci, 2015, 16 (10): 25744- 25758
doi: 10.3390/ijms161025744
31 DALVI P , SHARMA H , CHINNAPPAN M et al. Enhanced autophagy in pulmonary endothelial cells on exposure to HIV-Tat and morphine:role in HIV-related pulmonary arterial hypertension[J]. Autophagy, 2016, 12 (12): 2420- 2438
doi: 10.1080/15548627.2016.1238551
32 SALABEI J K , CUMMINS T D , SINGH M et al. PDGF-mediated autophagy regulates vascular smooth muscle cell phenotype and resistance to oxidative stress[J]. Biochem J, 2013, 451 (3): 375- 388
doi: 10.1042/BJ20121344
33 ZHENG Y H , TIAN C , MENG Y et al. Osteopontin stimulates autophagy via integrin/CD44 and p38 MAPK signaling pathways in vascular smooth muscle cells[J]. J Cell Physiol, 2012, 227 (1): 127- 135
doi: 10.1002/jcp.22709
34 HA J M , YUN S J , KIM Y W et al. Platelet-derived growth factor regulates vascular smooth muscle phenotype via mammalian target of rapamycin complex 1[J]. Biochem Biophys Res Commun, 2015, 464 (1): 57- 62
doi: 10.1016/j.bbrc.2015.05.097
35 LEE S J , SMITH A , GUO L et al. Autophagic protein LC3B confers resistance against hypoxia-induced pulmonary hypertension[J]. Am J Respir Crit Care Med, 2011, 183 (5): 649- 658
doi: 10.1164/rccm.201005-0746OC
36 SAVAI R , AL-TAMARI H M , SEDDING D et al. Pro-proliferative and inflammatory signaling converge on FoxO1 transcription factor in pulmonary hypertension[J]. Nat Med, 2014, 20 (11): 1289- 1300
doi: 10.1038/nm.3695
37 SALABEI J K , BALAKUMARAN A , FREY J C et al. Verapamil stereoisomers induce antiproliferative effects in vascular smooth muscle cells via autophagy[J]. Toxicol Appl Pharmacol, 2012, 262 (3): 265- 272
doi: 10.1016/j.taap.2012.04.036
38 LONG L , YANG X , SOUTHWOOD M et al. Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type Ⅱ receptor degradation[J]. Circ Res, 2013, 112 (8): 1159- 1170
doi: 10.1161/CIRCRESAHA.111.300483
39 TENG R J , DU J , WELAK S et al. Cross talk between NADPH oxidase and autophagy in pulmonary artery endothelial cells with intrauterine persistent pulmonary hypertension[J]. Am J Physiol Lung Cell Mol Physiol, 2012, 302 (7): L651- L663
doi: 10.1152/ajplung.00177.2011
40 YANDRAPALLI S , TARIQ S , KUMAR J et al. Chronic thromboembolic pulmonary hypertension:epidemiology, diagnosis, and management[J]. Cardiol Rev, 2018, 26 (2): 62- 72
41 DENG C , WU D , YANG M et al. The role of tissue factor and autophagy in pulmonary vascular remodeling in a rat model for chronic thromboembolic pulmonary hypertension[J]. Respir Res, 2016, 17 (1): 65
doi: 10.1186/s12931-016-0383-y
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