药学学报, 2019, 54(4): 611-619
引用本文:
贺启莲, 格日力, 李占强, 芦殿香. 高原适应遗传学缺氧诱导因子通路相关基因及其药理学研究进展[J]. 药学学报, 2019, 54(4): 611-619.
HE Qi-lian, GE Ri-li, LI Zhan-qiang, LU Dian-xiang. Hypoxia inducing factor related genetic adaptation in high-altitude and pharmacological modulation[J]. Acta Pharmaceutica Sinica, 2019, 54(4): 611-619.

高原适应遗传学缺氧诱导因子通路相关基因及其药理学研究进展
贺启莲1,2,3, 格日力1,2, 李占强1,2, 芦殿香1,2
1. 青海大学高原医学研究中心, 青海 西宁 810001;
2. 青海大学青海省高原医学应用基础重点实验室, 青海-犹他高原医学联合重点实验室, 青海 西宁 810001;
3. 青海大学医学院临床医学系, 青海 西宁 810001
摘要:
人类对高原缺氧环境的适应表现、机制及相关药理学研究一直是科研探索的热点。一个世纪以来,主要集中于青藏高原、南美洲安第斯高原和埃塞俄比亚高原的高原世居人群对于慢性缺氧所具有的独特生理适应已经得到了科学验证,而近10年来的基因研究也证实高原适应具有遗传学基础,尤其与缺氧诱导因子(hypoxia inducible factor,HIF)通路及缺氧反应基因(hypoxia response elements,HREs)具有密切关系。但有趣的是,对高原缺氧的适应表现和遗传机制在上述三大高原世居人群中却并不完全相同,其中西藏人具有更好的高原适应表现,并且HIF通路是其最关键的适应机制。同时,由于HIF通路涉及广泛,可调节数以百计的下游基因表达,并与癌症、炎症、缺血、急性脏器损伤和感染等多种疾病密切相关,因此HIF通路的激活剂和抑制剂研究也取得了很大进展。本文就三大高原世居人群对高原环境的不同适应反应、HIF及HREs在不同种族高原适应中的遗传学作用机制、HIF通路的药理学研究进展进行了综述,以期为高原低氧遗传性适应及HIF相关性疾病的进一步研究提供参考。
关键词:    缺氧      高原      适应      缺氧诱导因子      脯氨酸羟化酶     
Hypoxia inducing factor related genetic adaptation in high-altitude and pharmacological modulation
HE Qi-lian1,2,3, GE Ri-li1,2, LI Zhan-qiang1,2, LU Dian-xiang1,2
1. Research Center for High Altitude Medicine, Qinghai University, Xining 810001, China;
2. Key Laboratory of Application and Foundation for High Altitude, Medicine Research in Qinghai Province, Qinghai-Utah Joint Research key Laboratory for High Altitude Medicine, Qinghai University, Xining 810001, China;
3. Medical Department, Medical College, Qinghai University, Xining 810001, China
Abstract:
Adaptation to hypoxia of the plateau environment has been a focus of scientific research in decades. The geographical distributions of such living environment include the Qinghai-Tibet Plateau, Andean Plateau in South America and Ethiopian Plateau. Over the past century, the unique features of physiological adaptation to high-altitude chronic hypoxia have been documented scientifically. The genetic studies of hypoxic adaptation in the past decade have revealed genetic bases of human high-altitude adaptation, with a close relationship to the hypoxia inducible factor (HIF) pathway and hypoxia response elements (HREs). Interestingly, the genetic pattern of adaptation to hypoxia is not the same among the three plateau populations. Tibetan has developed the best high-altitude adaptation, with modification of the HIF pathway as the key genetic element. Due to the wide range of HIF pathways, HIFs could regulate hundreds of downstream genes and are closely related to various diseases such as cancer, inflammation, ischemia, acute organ damage and infection, etc. The treatment researches of these diseases through HIFs-related regulations have led to the development of stabilizers and inhibitors of HIF pathway. We review here the adaptive responses of the three plateau populations to the hypoxic environment, and the genetic mechanism of HIF and HREs in the different ethnic high-altitude populations. Classes of HIF inhibitors, such as PI3K and/or mammalian target of rapamycin (mTOR) inhibitors, DNA-binding inhibitors, histone deacetylase inhibitors, heat-shock protein 90 inhibitors, cardiac glycosides, transcription inhibitors, topoisomerase inhibitors, and HIF activators including 2-OG mimics, Fe2+ chelators, prolyl hydroxylase (PHD) active-site blockers and CUL2 deneddylators have been presented with the drug examples. In addition, the top 3 chemical-disease and chemical-gene (protein) co-occurrences have been presented from the Pubmed literature search. The review could serve as references for research of hypoxia adaptation and HIF-related diseases.
Key words:    hypoxia    altitude    adaptation    hypoxia-inducible factor    prolyl hydroxylases domain   
收稿日期: 2019-01-04
DOI: 10.16438/j.0513-4870.2019-0010
基金项目: 国家自然科学基金资助项目(81860768,81660308).
通讯作者: 李占强, 芦殿香
Email: zhanqiang_li@163.com;ludianxiang@qhu.edu.cn
相关功能
PDF(409KB) Free
打印本文
0
作者相关文章
贺启莲  在本刊中的所有文章
格日力  在本刊中的所有文章
李占强  在本刊中的所有文章
芦殿香  在本刊中的所有文章

参考文献:
[1] Beall CM. Human adaptability studies at high altitude:research designs and major concepts during fifty years of discovery[J]. Am J Hum Biol, 2013, 25:141-147.
[2] Risso A, Fabbro D, Damante G, et al. Expression of fetal hemoglobin in adult humans exposed to high altitude hypoxia[J]. Blood Cells Mol Dis, 2012, 48:147-153.
[3] Villafuerte FC. New genetic and physiological factors for excessive erythrocytosis and chronic mountain sickness[J]. J Appl Physiol, 2015, 119:1481-1486.
[4] Sarna K, Gebremedin A, Brittenham GM, et al. WHO hemoglobin thresholds for altitude increase the prevalence of anemia among Ethiopian highlanders[J]. Am J Hematol, 2018, 93:E229-E231.
[5] Beall CM, Decker MJ, Brittenham GM, et al. An Ethiopian pattern of human adaptation to high-altitude hypoxia[J]. Proc Natl Acad Sci U S A, 2002, 99:17215-17218.
[6] Weitz CA, Garruto RM. A comparative analysis of arterial oxygen saturation among Tibetans and Han born and raised at high altitude[J]. High Alt Med Biol, 2007, 8:13-26.
[7] Carter AM. Placental gas exchange and the oxygen supply to the fetus[J]. Compr Physiol, 2015, 5:1381-1403.
[8] Gilbert-Kawai ET, Milledge JS, Grocott MP, et al. King of the mountains:Tibetan and Sherpa physiological adaptations for life at high altitude[J]. Physiology (Bethesda), 2014, 29:388-402.
[9] Moore LG. Measuring high-altitude adaptation[J]. J Appl Physiol, 2017, 123:1371-1385.
[10] Beall CM. Andean, Tibetan, and Ethiopian patterns of adaptation to high-altitude hypoxia[J]. Integr Comp Biol, 2006, 46:18-24.
[11] Bigham AW, Wilson MJ, Julian CG, et al. Andean and Tibetan patterns of adaptation to high altitude[J]. Am J Hum Biol, 2013, 25:190-197.
[12] Talbot NP, Robbins PA, Dorrington KL. Changes in pulmonary vascular responsiveness to hypoxia[J]. Exp Physiol, 2017, 102:1561.
[13] Wilkins MR, Ghofrani HA, Weissmann N, et al. Pathophysiology and treatment of high-altitude pulmonary vascular disease[J]. Circulation, 2015, 131:582-590.
[14] Bigham AW, Julian CG, Wilson MJ, et al. Maternal PRKAA1and EDNRA genotypes are associated with birth weight, and PRKAA1with uterine artery diameter and metabolic homeostasis at high altitude[J]. Physiol Genomics, 2014, 46:687-697.
[15] Moore LG, Charles SM, Julian CG. Humans at high altitude:hypoxia and fetal growth[J]. Respir Physiol Neurobiol, 2011, 178:181-190.
[16] Soria R, Julian CG, Vargas E, et al. Graduated effects of high-altitude hypoxia and highland ancestry on birth size[J]. Pediatr Res, 2013, 74:633-638.
[17] Summerfield DT,Coffman KE, Taylor BJ, et al. Exhaled nitric oxide changes during acclimatization to high altitude:a descriptive study[J]. High Alt Med Biol, 2018, 19:215-220.
[18] Vozdek R, Long Y, Ma DK. The receptor tyrosine kinase HIR-1 coordinates HIF-independent responses to hypoxia and extracellular matrix injury[J]. Sci Signal, 2018.DOI:10.1126/scisignal.aat0138.
[19] Lendahl U, Lee KL, Yang H, et al. Generating specificity and diversity in the transcriptional response to hypoxia[J]. Nat Rev Genet, 2009, 10:821-832.
[20] Cowburn AS, Takeda N, Boutin AT, et al. HIF isoforms in the skin differentially regulate systemic arterial pressure[J]. Proc Natl Acad Sci U S A, 2013, 110:17570-17575.
[21] Koivunen P, Serpi R, Dimova EY. Hypoxia-inducible factor prolyl 4-hydroxylase inhibition in cardiometabolic diseases[J]. Pharmacol Res, 2016, 114:265-273.
[22] Ebersole JL, Novak MJ, Orraca L, et al. Hypoxia-inducible transcription factors, HIF1A and HIF2A, increase in aging mucosal tissues[J]. Immunology, 2018, 154:452-464.
[23] Franke K, Gassmann M, Wielockx B. Erythrocytosis:the HIF pathway in control[J]. Blood, 2013, 122:1122-1128.
[24] Perrotta S, Stiehl DP, Punzo F, et al. Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range[J]. Haematologica, 2013, 98:1624-1632.
[25] Gardie B, Percy MJ, Hoogewijs D, et al. The role of PHD2 mutations in the pathogenesis of erythrocytosis[J]. Hypoxia (Auckl), 2014, 2:71-90.
[26] Jia HZ, Kasim V, Xu ZL, et al. Hypoxia-responsive factor PHD2 and angiogenic diseases[J]. Acta Pharm Sin (药学学报), 2014, 49:151-157.
[27] Bigham A, Bauchet M, Pinto D, et al. Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data[J]. PLoS Genet, 2010, 6:e1001116.
[28] Simonson TS, McClain DA, Jorde LB, et al. Genetic determinants of Tibetan high-altitude adaptation[J]. Hum Genet, 2012, 131:527-533.
[29] Wang B, Zhang YB, Zhang F, et al. On the origin of Tibetans and their genetic basis in adapting high-altitude environments[J]. PLoS One, 2011, 6:e17002.
[30] Petousi N, Robbins PA. Human adaptation to the hypoxia of high altitude:the Tibetan paradigm from the pregenomic to the postgenomic era[J]. J Appl Physiol, 2014, 116:875-884.
[31] Beall CM, Cavalleri GL, Deng L, et al. Natural selection on EPAS1(HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders[J]. Proc Natl Acad Sci U S A, 2010, 107:11459-11464.
[32] Yi X, Liang Y, Huerta-Sanchez E, et al. Sequencing of 50 human exomes reveals adaptation to high altitude[J]. Science, 2010, 329:75-78.
[33] Lorenzo FR, Huff C, Myllymaki M, et al. A genetic mechanism for Tibetan high-altitude adaptation[J]. Nat Genet, 2014, 46:951-956.
[34] Simonson TS, Yang Y, Huff CD, et al. Genetic evidence for high-altitude adaptation in Tibet[J]. Science, 2010, 329:72-75.
[35] Xiang K,Ouzhuluobu, Peng Y, et al. Identification of a Tibetan-specific mutation in the hypoxic gene EGLN1 and its contribution to high-altitude adaptation[J]. Mol Biol Evol, 2013, 30:1889-1898.
[36] Takeda N, O'Dea EL, Doedens A, et al. Differential activation and antagonistic function of HIF-alpha isoforms in macrophages are essential for NO homeostasis[J]. Genes Dev, 2010, 24:491-501.
[37] Zhou D, Udpa N, Ronen R, et al. Whole-genome sequencing uncovers the genetic basis of chronic mountain sickness in Andean highlanders[J]. Am J Hum Genet, 2013, 93:452-462.
[38] Udpa N, Ronen R, Zhou D, et al. Whole genome sequencing of Ethiopian highlanders reveals conserved hypoxia tolerance genes[J]. Genome Biol, 2014, 15:R36.
[39] Huerta-Sánchez E, DeGiorgio M, Pagani L, et al. Genetic signatures reveal high-altitude adaptation in a set of ethiopian populations[J]. Mol Biol Evol, 2013, 30:1877-1888.
[40] Scheinfeldt LB, Tishkoff SA. Recent human adaptation:genomic approaches, interpretation and insights[J]. Nat Rev Genet, 2013, 14:692-702.
[41] Azad P, Stobdan T, Zhou D, et al. High-altitude adaptation in humans:from genomics to integrative physiology[J]. J Mol Med (Berl), 2017, 95:1269-1282.
[42] Bigham AW. Genetics of human origin and evolution:high-altitude adaptations[J]. Curr Opin Genet Dev, 2016, 41:8-13.
[43] Jablonski NG. Genes for the high life:new genetic variants point to positive selection for high altitude hypoxia in Tibetans[J]. Zool Res, 2017, 38:117.
[44] Gupta N, Wish JB. Hypoxia-inducible factor prolyl hydroxylase inhibitors:a potential new treatment for anemia in patients with CKD[J]. Am J Kidney Dis, 2017, 69:815-826.
[45] Chen FF, Li XX, Sun L, et al. Advances in tumor microenvironment and related targeted drugs[J]. Acta Pharm Sin (药学学报), 2018, 53:676-683.
[46] Zou Y, Liu Y, Huang W, et al. Advances on anti-neoplastic STAT3 inhibitors[J]. Acta Pharm Sin (药学学报), 2018, 53:1598-1606.
[47] Eckle T, Brodsky K, Bonney M, et al. HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium[J]. PLoS Biol, 2013, 11:e1001665.
[48] Jiang BH, Jiang G, Zheng JZ, et al. Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1[J]. Cell Growth Differ, 2001, 12:363-369.
[49] Majumder PK, Febbo PG, Bikoff R, et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways[J]. Nat Med, 2004, 10:594-601.
[50] Kong D, Park EJ, Stephen AG, et al. Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity[J]. Cancer Res, 2005, 65:9047-9055.
[51] Mie Lee Y, Kim SH, Kim HS, et al. Inhibition of hypoxia-induced angiogenesis by FK228, a specific histone deacetylase inhibitor, via suppression of HIF-1alpha activity[J]. Biochem Biophys Res Commun, 2003, 300:241-246.
[52] Kong X, Lin Z, Liang D, et al. Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1alpha[J]. Mol Cell Biol, 2006, 26:2019-2028.
[53] Hur E, Kim HH, Choi SM, et al. Reduction of hypoxia-induced transcription through the repression of hypoxia-inducible factor-1alpha/aryl hydrocarbon receptor nuclear translocator DNA binding by the 90-kDa heat-shock protein inhibitor radicicol[J]. Mol Pharmacol, 2002, 62:975-982.
[54] Osada M, Imaoka S, Funae Y. Apigenin suppresses the expression of VEGF, an important factor for angiogenesis, in endothelial cells via degradation of HIF-1alpha protein[J]. FEBS Lett, 2004, 575:59-63.
[55] Mabjeesh NJ, Post DE, Willard MT, et al. Geldanamycin induces degradation of hypoxia-inducible factor 1alpha protein via the proteosome pathway in prostate cancer cells[J]. Cancer Res, 2002, 62:2478-2482.
[56] Zhang H, Qian DZ, Tan YS, et al. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth[J]. Proc Natl Acad Sci U S A, 2008, 105:19579-19586.
[57] Yeo EJ, Ryu JH, Cho YS, et al. Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1[J]. Blood, 2006, 107:916-923.
[58] Kung AL, Zabludoff SD, France DS, et al. Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway[J]. Cancer Cell, 2004, 6:33-43.
[59] Verma RP, Hansch C. Camptothecins:a SAR/QSAR study[J]. Chem Rev, 2009, 109:213-235.
[60] Rapisarda A, Zalek J, Hollingshead M, et al. Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts[J]. Cancer Res, 2004, 64:6845-6848.
[61] Bernhardt WM, Gottmann U, Doyon F, et al. Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model[J]. Proc Natl Acad Sci U S A, 2009, 106:21276-21281.
[62] Adamcio B, Sperling S, Hagemeyer N, et al. Hypoxia inducible factor stabilization leads to lasting improvement of hippocampal memory in healthy mice[J]. Behav Brain Res, 2010, 208:80-84.
[63] Fraisl P, Mazzone M, Schmidt T, et al. Regulation of angiogenesis by oxygen and metabolism[J]. Dev Cell, 2009, 16:167-179.
[64] Wu YJ, Fang LH, Du GH. Advance in the study of myocardial ischemic preconditioning and postconditioning and the clinical applications[J]. Acta Pharm Sin (药学学报), 2013, 48:965-970.
[65] Bernhardt WM, Wiesener MS, Scigalla P, et al. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD[J]. J Am Soc Nephrol, 2010, 21:2151-2156.
[66] Rey S, Lee K, Wang CJ, et al. Synergistic effect of HIF-1alpha gene therapy and HIF-1-activated bone marrow-derived angiogenic cells in a mouse model of limb ischemia[J]. Proc Natl Acad Sci U S A, 2009, 106:20399-20404.
[67] Aragones J, Schneider M, Van Geyte K, et al. Deficiency or inhibition of oxygen sensor PHD1 induces hypoxia tolerance by reprogramming basal metabolism[J]. Nat Genet, 2008, 40:170-180.
[68] Chan DA, Sutphin PD, Denko NC, et al. Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1alpha[J]. J Biol Chem, 2002, 277:40112-40117.
[69] McDonough MA, McNeill LA, Tilliet M, et al. Selective inhibition of factor inhibiting hypoxia-inducible factor[J]. J Am Chem Soc, 2005, 127:7680-7681.
[70] Wang GL, Semenza GL. Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity:implications for models of hypoxia signal transduction[J]. Blood, 1993, 82:3610-3615.
[71] Knowles HJ, Tian YM, Mole DR, et al. Novel mechanism of action for hydralazine:induction of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and angiogenesis by inhibition of prolyl hydroxylases[J]. Circ Res, 2004, 95:162-169.
[72] Nangaku M, Izuhara Y, Takizawa S, et al. A novel class of prolyl hydroxylase inhibitors induces angiogenesis and exerts organ protection against ischemia[J]. Arterioscler Thromb Vasc Biol, 2007, 27:2548-2554.
[73] Zaman K, Ryu H, Hall D, et al. Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-1 and ATF-1/CREB and increased expression of glycolytic enzymes, p21(waf1/cip1), and erythropoietin[J]. J Neurosci, 1999, 19:9821-9830.
[74] Warshakoon NC, Wu S, Boyer A, et al. Design and synthesis of a series of novel pyrazolopyridines as HIF-1alpha prolyl hydroxylase inhibitors[J]. Bioorg Med Chem Lett, 2006, 16:5687-5690.
[75] Choi SM, Choi KO, Park YK, et al. Clioquinol, a Cu(Ⅱ)/Zn(Ⅱ) chelator, inhibits both ubiquitination and asparagine hydroxylation of hypoxia-inducible factor-1alpha, leading to expression of vascular endothelial growth factor and erythropoietin in normoxic cells[J]. J Biol Chem, 2006, 281:34056-34063.
[76] Ehrentraut SF, Kominsky DJ,Glover LE, et al. Central role for endothelial human deneddylase-1/SENP8 in fine-tuning the vascular inflammatory response[J]. J Immunol, 2013, 190:392-400.
相关文献:
1.罗冰峰, 张俊, 杨涛, 张娟红, 李文斌, 王昌, 张明霞, 王荣.高原急性缺氧对大鼠药物转运体PEPT1及阿莫西林药代动力学的影响[J]. 药学学报, 2017,52(11): 1715-1721
2.连浦峤, 范燕楠, 杨慧, 傅丽霞, 李云霄, 侯琦.二苯乙烯苷通过MAPK、HIF-1α和p53通路减轻缺氧/复氧损伤诱导的支气管上皮细胞凋亡[J]. 药学学报, 2017,52(7): 1122-1132
3.邱水平, 李鸿丽, 石海莲, 吴辉, 黄菲, 张蓓蓓, 吴晓俊, 王峥涛.三七皂苷Ft1抑制乳腺癌细胞增殖、迁移及促进凋亡的机制研究[J]. 药学学报, 2016,51(7): 1091-1097
4.来芳芳, 牛非, 杨瀚泽, 周琬琪, 陈晓光.以HIF-1α和P300相互作用为靶点的抑制剂筛选模型的建立[J]. 药学学报, 2014,49(6): 849-853
5.来芳芳, 刘晓宇, 牛非, 郎立伟, 谢平, 陈晓光.新型HIF-1抑制剂三白脂素-8衍生物LXY6099的抗肿瘤作用[J]. 药学学报, 2014,49(5): 622-626
6.徐红瑞,林 波,王思谦,张 挚,路晓霞,刘 悦,皇甫超申.亚硝酸钠对H22荷瘤小鼠移植瘤上皮-间质转化的促进作用[J]. 药学学报, 2012,47(11): 1470-1476
7.闫文义, 于东明, 皇甫超申.亚硝酸钠诱导PC12细胞分化[J]. 药学学报, 2012,47(9): 1147-1152
8.连泽勤;赵大龙;朱海波.羟基红花黄色素A上调低氧状态下血管内皮细胞中缺氧诱导因子-1α的表达[J]. 药学学报, 2008,43(5): 484-489
9.王敬俭;李静;耿美玉.靶向缺氧诱导因子-1的抗肿瘤药物研究进展[J]. 药学学报, 2008,43(6): 565-569
10.傅颖君;何明.阿魏酸钠对心肌细胞缺氧/复氧损伤的保护作用及其机制[J]. 药学学报, 2004,39(5): 325-327
11.连浦峤, 范燕楠, 杨慧, 傅丽霞, 李云霄, 侯琦.二苯乙烯苷通过MAPK、HIF-1α和p53通路减轻缺氧/复氧损伤诱导的支气管上皮细胞凋亡[J]. 药学学报,