|本期目录/Table of Contents|

[1]颜艺,王晓建,荆志成.肺动脉高压遗传学研究新进展[J].慢性病学杂志,2015,(01):52-56.
点击复制

肺动脉高压遗传学研究新进展(PDF)

《慢性病学杂志》[ISSN:1674-8166/CN:11-5900/R]

卷:
期数:
2015年01期
页码:
52-56
栏目:
综述
出版日期:
2015-01-29

文章信息/Info

Title:
-
作者:
颜艺1;  王晓建2;  荆志成2
1.同济大学附属上海市肺科医院，上海200433； 2.中国医学科学院，北京协和医学院，国家心血管病中心，阜外心血管病医院，心血管疾病国家重点实验室， 血栓性疾病诊疗中心，北京100037
Author(s):
-
关键词:
特发性肺动脉高压; 遗传性肺动脉高压; 转化生长因子β; 发病机制
Keywords:
-
分类号:
R543.2
DOI:
-
摘要:
肺动脉高压（pulmonary arterial hypertension，PAH） 是一类以肺血管阻力进行性增高为特征的恶性 心血管病，最终导致右心衰竭及死亡。PAH 的病理机制至今仍不清楚，但已有大量证据表明遗传因素在该 疾病的发生发展中起重要作用。早期PAH 的遗传学研究多集中在转化生长因子（TGF-β） 信号通路。该 通路的多个重要基因（BMPR2、ALK1、ENG、SMAD9） 的遗传变异已被证实是遗传性PAH 和特发性 PAH 的致病因素。近年来，随着遗传学研究技术的进步，多个新的非TGF-β通路PAH 致病基因或修饰基 因被陆续发现，包括CAV1、KCNK3、TopB、P1CBLN2 等。这些疾病基因的发现加深了对PAH 的遗传 机制的认识，也为PAH 的个体化诊疗提供了新的可能。
Abstract:
-

参考文献/References:

[1] Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hyper? tension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the Interna? tional Society of Heart and Lung Transplantation (ISHLT) ［J］．Eur Heart J, 2009,30(20):2493-2537.
[2］ Benza RL, Miller DP, Barst RJ, et al. An evaluation of longterm survival from time of diagnosis in pulmonary arterial hy? pertension from the REVEAL Registry ［J］．Chest, 2012,142 (2):448-456.
[3］ Deng Z, Morse JH, Slager SL, et al. Familial primary pulmo? nary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene ［J］．Am J Hum Genet, 2000,67(3):737-744.
[4］ Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous germline mutations in BMPR2, encoding a TGF- beta recep? tor, cause familial primary pulmonary hypertension ［J］． Nat Genet, 2000,26(1):81-84.
[5］ Aldred MA, Vijayakrishnan J, James V, et al. BMPR2 gene rearrangements account for a significant proportion of muta? tions in familial and idiopathic pulmonary arterial hypertension ［J］．Hum Mutat, 2006,27(2):212-213.
[6］ Cogan JD, Pauciulo MW, Batchman AP, et al. High frequen? cy of BMPR2 exonic deletions/duplications in familial pulmo? nary arterial hypertension ［J］． Am J Respir Crit Care Med, 2006,174(5):590-598.
[7］ Cogan JD, Vnencak- Jones CL, Phillips JA 3rd, et al. Gross BMPR2 gene rearrangements constitute a new cause for prima? ry pulmonary hypertension ［J］．Genet Med, 2005,7(3):169- 174.
[8］ Liu D, Liu QQ, Eyries M, et al. Molecular genetics and clini? cal features of Chinese idiopathic and heritable pulmonary arte? rial hypertension patients ［J］．Eur Respir J, 2012,39(3):597- 603.
[9］ Phillips JA 3rd, Poling JS, Phillips CA, et al. Synergistic het? erozygosity for TGFbeta1 SNPs and BMPR2 mutations modu? lates the age at diagnosis and penetrance of familial pulmonary arterial hypertension ［J］．Genet Med, 2008,10(5):359-365.
[10］ Sztrymf B, Coulet F, Girerd B, et al. Clinical outcomes of pul? monary arterial hypertension in carriers of BMPR2 mutation ［J］． Am J Respir Crit Care Med, 2008,177(12):1377-1383.
[11］ Liu D, Wu WH, Mao YM, et al. BMPR2 mutations influence phenotype more obviously in male patients with pulmonary ar? terial hypertension ［J］． Circ Cardiovasc Genet, 2012,5(5): 511-518.
[12］ Humbert M, Deng Z, Simonneau G, et al. BMPR2 germline mutations in pulmonary hypertension associated with fenflura? mine derivatives ［J］． Eur Respir J, 2002,20(3):518-523.
[13］ Roberts KE, McElroy JJ, Wong WP, et al. BMPR2 muta? tions in pulmonary arterial hypertension with congenital heart disease ［J］． Eur Respir J, 2004,24(3):371-374.
[14］ Feng YX, Liu D, Sun ML, et al. BMPR2 germline mutation in chronic thromboembolic pulmonary hypertension ［J］ ． Lung,2014,192(4):625-627.
[15］ Machado RD, Eickelberg O, Elliott CG, et al. Genetics and genomics of pulmonary arterial hypertension ［J］． J Am Coll Cardiol, 2009,54(1 Suppl):S32-42.
[16］ Machado RD, Pauciulo MW, Thomson JR, et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for pri? mary pulmonary hypertension ［J］．Am J Hum Genet, 2001, 68(1):92-102.
[17］ Morse JH, Jones AC, Barst RJ, et al. Familial primary pulmo? nary hypertension locus mapped to chromosome 2q31- q32 ［J］．Chest, 1998,114(1 Suppl):57S-58S.
[18］ Trell E, Johansson BW, Linell F, et al. Familial pulmonary hypertension and multiple abnormalities of large systemic arter? ies in Osler's disease ［J］．Am J Med, 1972,53(1):50-63.
[19］ Harrison RE, Flanagan JA, Sankelo M, et al. Molecular and functional analysis identifies ALK- 1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia ［J］．J Med Genet, 2003,40(12):865-871.
[20］ Abdalla SA, Gallione CJ, Barst RJ, et al. Primary pulmonary hypertension in families with hereditary haemorrhagic telangi? ectasia ［J］．Eur Respir J, 2004,23(3):373-377.
[21］ Girerd B, Montani D, Coulet F, et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation ［J］． Am J Respir Crit Care Med, 2010,181(8):851-861.
[22］ Chen YJ, Yang QH, Liu D, et al. Clinical and genetic charac? teristics of Chinese patients with hereditary haemorrhagic telan? giectasia- associated pulmonary hypertension ［J］． Eur J Clin Invest, 2013,43(10):1016-1024.
[23］ Trembath RC, Thomson JR, Machado RD, et al. Clinical and molecular genetic features of pulmonary hypertension in pa? tients with hereditary hemorrhagic telangiectasia ［J］． N Engl J Med, 2001,345(5):325-334.
[24］ Spiekerkoetter E, Tian X, Cai J, et al. FK506 activates BM ? PR2, rescues endothelial dysfunction, and reverses pulmonary hypertension ［J］． J Clin Invest, 2013,123(8):3600-3613.
[25］ Reynolds AM, Xia W, Holmes MD, et al. Bone morphogenet? ic protein type 2 receptor gene therapy attenuates hypoxic pul? monary hypertension ［J］．Am J Physiol Lung Cell Mol Physi? ol, 2007,292(5):L1182-1192.
[26］ Reynolds AM, Holmes MD, Danilov SM, et al. Targeted gene delivery of BMPR2 attenuates pulmonary hypertension ［J］． Eur Respir J, 2012,39(2):329-343.
[27］ Drake KM, Dunmore BJ, McNelly LN, et al. Correction of nonsense BMPR2 and SMAD9 mutations by ataluren in pul? monary arterial hypertension ［J］．Am J Respir Cell Mol Biol, 2013,49(3):403-409.
[28］ Long L, Crosby A, Yang X, et al. Altered bone morphogenet? ic protein and transforming growth factor- beta signaling in rat models of pulmonary hypertension: potential for activin recep? tor- like kinase- 5 inhibition in prevention and progression of disease ［J］．Circulation, 2009,119(4):566-576.
[29］ Ogo T, Chowdhury HM, Yang J, et al. Inhibition of overac? tive transforming growth factor-β signaling by prostacyclin an? alogs in pulmonary arterial hypertension ［J］． Am J Respir Cell Mol Biol, 2013,48(6):733-741.
[30］ Yang J, Li X, Al-Lamki RS, et al. Sildenafil potentiates bone morphogenetic protein signaling in pulmonary arterial smooth muscle cells and in experimental pulmonary hypertension ［J］． Arterioscler Thromb Vasc Biol, 2013,33(1):34-42.
[31］ Sztrymf B, Yaici A, Girerd B, et al. Genes and pulmonary ar? terial hypertension ［J］．Respiration, 2007,74(2):123-132.
[32］ Austin ED, Ma L, LeDuc C, et al. Whole exome sequencing to identify a novel gene (caveolin- 1) associated with human pulmonary arterial hypertension ［J］． Circ Cardiovasc Genet, 2012,5(3):336-343.
[33］ Minshall RD, Sessa WC, Stan RV, et al. Caveolin regulation of endothelial function ［J］． Am J Physiol Lung Cell Mol Physiol, 2003,285(6):L1179-1183.
[34］ Mathew R, Huang J, Shah M, et al. Disruption of endothelialcell caveolin- 1alpha/raft scaffolding during development of monocrotaline-induced pulmonary hypertension ［J］．Circula? tion, 2004,110(11):1499-1506.
[35］ Maniatis NA, Shinin V, Schraufnagel DE, et al. Increased pulmonary vascular resistance and defective pulmonary artery filling in caveolin- 1-/- mice ［J］． Am J Physiol Lung Cell Mol Physiol, 2008,294(5):L865-873.
[36］ Zhao YY, Liu Y, Stan RV, et al. Defects in caveolin- 1 cause dilated cardiomyopathy and pulmonary hypertension in knock? out mice ［J］． Proc Natl Acad Sci U S A, 2002,99(17): 11375-11380.
[37］ Zhao YY, Zhao YD, Mirza MK, et al. Persistent eNOS acti? vation secondary to caveolin- 1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration ［J］． J Clin Invest, 2009,119(7):2009-2018.
[38］ Shiroto T, Romero N, Sugiyama T, et al. Caveolin-1 is a crit? ical determinant of autophagy, metabolic switching, and oxida? tive stress in vascular endothelium ［J］． PLoS One, 2014,9 (2):e87871.
[39］ Long L, Yang X, Southwood M, et al. Chloroquine prevents progression of experimental pulmonary hypertension via inhibi? tion of autophagy and lysosomal bone morphogenetic protein type II receptor degradation ［J］． Circ Res, 2013,112(8): 1159-1170.
[40］ Asterholm IW, Mundy DI, Weng J, et al. Altered mitochon? drial function and metabolic inflexibility associated with loss of caveolin-1 ［J］ . Cell Metab, 2012,15(2):171-185.
[41］ Jasmin JF, Mercier I, Dupuis J, et al. Short-term administra? tion of a cell-permeable caveolin-1 peptide prevents the devel?opment of monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy ［J］． Circulation, 2006,114(9): 912-920.
[42］ Ma L, Roman- Campos D, Austin ED, et al. A novel chan? nelopathy in pulmonary arterial hypertension ［J］． N Engl J Med, 2013,369(4):351-361.
[43］ Gurney AM, Osipenko ON, MacMillan D, et al. Two- pore domain K channel, TASK- 1, in pulmonary artery smooth muscle cells ［J］．Circ Res, 2003,93(10):957-964.
[44］ Olschewski A, Li Y, Tang B, et al. Impact of TASK-1 in hu? man pulmonary artery smooth muscle cells ［J］． Circ Res, 2006,98(8):1072-1080.
[45］ Tang B, Li Y, Nagaraj C, et al. Endothelin- 1 inhibits back? ground two- pore domain channel TASK- 1 in primary human pulmonary artery smooth muscle cells ［J］． Am J Respir Cell Mol Biol, 2009,41(4):476-483.
[46］ Seyler C, Duthil- Straub E, Zitron E, et al. TASK1 (K(2P) 3.1) K(+ ) channel inhibition by endothelin- 1 is mediated through Rho kinase- dependent phosphorylation ［J］． Br J Pharmacol, 2012,165(5):1467-1475.
[47］ Trapp S, Aller MI, Wisden W, et al. A role for TASK- 1 (KCNK3) channels in the chemosensory control of breathing ［J］．J Neurosci, 2008,28(35):8844-8850.
[48］ de Jesus Perez VA, Yuan K, Lyuksyutova MA, et al. Wholeexome sequencing reveals TopBP1 as a novel gene in idiopath? ic pulmonary arterial hypertension ［J］．Am J Respir Crit Care Med, 2014,189(10):1260-1272.
[49］ Meloche J, Pflieger A, Vaillancourt M, et al. Role for DNA damage signaling in pulmonary arterial hypertension ［J］．Cir? culation, 2014,129(7):786-797.
[50］ Garcia V, Furuya K, Carr AM. Identification and functional analysis of TopBP1 and its homologs ［J］． DNA Repair (Amst), 2005,4(11):1227-1239.
[51］ Ren B, Cam H, Takahashi Y, et al. E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M check? points ［J］．Genes Dev, 2002,16(2):245-256.
[52］ Li M, Vattulainen S, Aho J, et al. Loss of bone morphogenetic protein receptor 2 is associated with abnormal DNA repair in pulmonary arterial hypertension ［J］． Am J Respir Cell Mol Biol, 2014,50(6):1118-1128.
[53］ Makiniemi M, Hillukkala T, Tuusa J, et al. BRCT domaincontaining protein TopBP1 functions in DNA replication and damage response ［J］． J Biol Chem, 2001,276(32):30399- 30406.
[54］ Yamane K, Chen J, Kinsella TJ. Both DNA topoisomerase IIbinding protein 1 and BRCA1 regulate the G2- M cell cycle checkpoint ［J］．Cancer Res, 2003,63(12):3049-3053.
[55］ Germain M, Eyries M, Montani D, et al. Genome-wide asso? ciation analysis identifies a susceptibility locus for pulmonary arterial hypertension ［J］．Nat Genet, 2013,45(5):518-521.

备注/Memo

备注/Memo:
基金项目：国家自然科学基金资助项目（81320108005）； 北京市自然科学基金资助项目（7141009） 作者简介：颜艺，博士研究生，主要从事心血管内科工作 通信作者：王晓建，E-mail: wang_xiaojian@vip.163.com
更新日期/Last Update: 2015-01-15