期刊论文详细信息
BMC Systems Biology
Insights from systems pharmacology into cardiovascular drug discovery and therapy
Yonghua Wang1  Ling Yang3  Aiping Lu2  Pidong Li1  Xuetong Chen1  Chunli Zheng1  Jiangfeng Du4  Chao Huang1  Jinlong Ru1  Yingxue Fu1  Peng Li1 
[1] Center of Bioinformatics, College of Life Science, Northwest A and F University, Yang ling 712100, Shaanxi, China;School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong;Lab of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning, China;Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
关键词: Gene-disease network;    Drug-target network;    Drug discovery;    Network analysis;    Network pharmacology;    Cardiovascular disease;   
Others  :  1091078
DOI  :  10.1186/s12918-014-0141-z
 received in 2014-07-25, accepted in 2014-12-11,  发布年份 2014
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【 摘 要 】

Background

Given the complex nature of cardiovascular disease (CVD), information derived from a systems-level will allow us to fully interrogate features of CVD to better understand disease pathogenesis and to identify new drug targets.

Results

Here, we describe a systematic assessment of the multi-layer interactions underlying cardiovascular drugs, targets, genes and disorders to reveal comprehensive insights into cardiovascular systems biology and pharmacology. We have identified 206 effect-mediating drug targets, which are modulated by 254 unique drugs, of which, 43% display activities across different protein families (sequence similarity < 30%), highlighting the fact that multitarget therapy is suitable for CVD. Although there is little overlap between cardiovascular protein targets and disease genes, the two groups have similar pleiotropy and intimate relationships in the human disease gene-gene and cellular networks, supporting their similar characteristics in disease development and response to therapy. We also characterize the relationships between different cardiovascular disorders, which reveal that they share more etiological commonalities with each other rooted in the global disease-disease networks. Furthermore, the disease modular analysis demonstrates apparent molecular connection between 227 cardiovascular disease pairs.

Conclusions

All these provide important consensus as to the cause, prevention, and treatment of various CVD disorders from systems-level perspective.

【 授权许可】

   
2014 Li et al.; licensee BioMed Central.

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【 参考文献 】
  • [1]Plump A: Accelerating the pulse of cardiovascular R&D. Nat Rev Drug Discov 2010, 9(11):823-824.
  • [2]Garber AM: An uncertain future for cardiovascular drug development? N Engl J Med 2009, 360(12):1169-1171.
  • [3]Marian AJ, Belmont J: Strategic approaches to unraveling genetic causes of cardiovascular diseases. Circ Res 2011, 108(10):1252-1269.
  • [4]Franco M, Cooper RS, Bilal U, Fuster V: Challenges and opportunities for cardiovascular disease prevention. Am J Med 2011, 124(2):95-102.
  • [5]Zhao S, Iyengar R: Systems pharmacology: network analysis to identify multiscale mechanisms of drug action. Annu Rev Pharmacol Toxicol 2012, 52:505-521.
  • [6]Xie L, Xie L, Kinnings SL, Bourne PE: Novel computational approaches to polypharmacology as a means to define responses to individual drugs. Annu Rev Pharmacol Toxicol 2012, 52:361-379.
  • [7]Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD: Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007, 357(21):2109-2122.
  • [8]Forrest MJ, Bloomfield D, Briscoe RJ, Brown P, Cumiskey AM, Ehrhart J, Hershey J, Keller W, Ma X, McPherson H: Torcetrapib‐induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol 2008, 154(7):1465-1473.
  • [9]Schönbeck U, Libby P: Inflammation, immunity, and HMG-CoA reductase inhibitors statins as antiinflammatory agents? Circulation 2004, 109(21 suppl 1):II18-II26.
  • [10]Yıldırım MA, Goh KI, Cusick ME, Barabási AL, Vidal M: Drug-target network. Nat Biotechnol 2007, 25(10):1119-1126.
  • [11]Chan SY, Loscalzo J: The emerging paradigm of network medicine in the study of human disease. Circ Res 2012, 111(3):359-374.
  • [12]Lage K, Greenway SC, Rosenfeld JA, Wakimoto H, Gorham JM, Segrè AV, Roberts AE, Smoot LB, Pu WT, Pereira AC: Genetic and environmental risk factors in congenital heart disease functionally converge in protein networks driving heart development. Proc Natl Acad Sci U S A 2012, 109(35):14035-14040.
  • [13]Park J, Lee DS, Christakis NA, Barabási AL: The impact of cellular networks on disease comorbidity. Mol Syst Biol 2009, 5:262.
  • [14]Knox C, Law V, Jewison T, Liu P, Ly S, Frolkis A, Pon A, Banco K, Mak C, Neveu V: DrugBank 3.0: a comprehensive resource for ‘omics’ research on drugs. Nucleic Acids Res 2011, 39(suppl 1):D1035-D1041.
  • [15]Zhu F, Shi Z, Qin C, Tao L, Liu X, Xu F, Zhang L, Song Y, Liu X, Zhang J: Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery. Nucleic Acids Res 2012, 40(D1):D1128-D1136.
  • [16]Hare D, Foster T: The Orange Book: the Food and Drug Administration's advice on therapeutic equivalence. Am Pharm 1990, 7:35.
  • [17]Hamosh A, Scott AF, Amberger JS, Bocchini CA, McKusick VA: Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res 2005, 33(suppl 1):D514-D517.
  • [18]Goh KI, Cusick ME, Valle D, Childs B, Vidal M, Barabási AL: The human disease network. Proc Natl Acad Sci U S A 2007, 104(21):8685-8690.
  • [19]Lipscomb CE: Medical subject headings (MeSH). Bull Med Libr Assoc 2000, 88(3):265.
  • [20]Bergholdt R, Størling ZM, Lage K, Karlberg EO, Ólason PÍ, Aalund M, Nerup J, Brunak S, Workman CT, Pociot F: Integrative analysis for finding genes and networks involved in diabetes and other complex diseases. Genome Biol 2007, 8(11):R253. BioMed Central Full Text
  • [21]Das J, Yu H: HINT: High-quality protein interactomes and their applications in understanding human disease. BMC Syst Biol 2012, 6(1):92. BioMed Central Full Text
  • [22]Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT: Gene Ontology: tool for the unification of biology. Nat Genet 2000, 25(1):25-29.
  • [23]Resnik P: Semantic similarity in a taxonomy: An information-based measure and its application to problems of ambiguity in natural language. J Artif Intell Res 2011, 11(1):95-130.
  • [24]Ovaska K, Laakso M, Hautaniemi S: Fast Gene Ontology based clustering for microarray experiments. BioData Min 2008, 1(1):11. BioMed Central Full Text
  • [25]Drake MT, Shenoy SK, Lefkowitz RJ: Trafficking of G protein–coupled receptors. Circ Res 2006, 99(6):570-582.
  • [26]Roth BL, Sheffler DJ, Kroeze WK: Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov 2004, 3(4):353-359.
  • [27]Knight ZA, Lin H, Shokat KM: Targeting the cancer kinome through polypharmacology. Nat Rev Cancer 2010, 10(2):130-137.
  • [28]Hopkins AL: Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol 2008, 4(11):682-690.
  • [29]Metz JT, Hajduk PJ: Rational approaches to targeted polypharmacology: creating and navigating protein–ligand interaction networks. Curr Opin Chem Biol 2010, 14(4):498-504.
  • [30]Zheng C, Han L, Yap C, Ji Z, Cao Z, Chen Y: Therapeutic targets: progress of their exploration and investigation of their characteristics. Pharmacol Rev 2006, 58(2):259-279.
  • [31]Schenone M, Dančík V, Wagner BK, Clemons PA: Target identification and mechanism of action in chemical biology and drug discovery. Nat Chem Biol 2013, 9(4):232-240.
  • [32]Dudley AM, Janse DM, Tanay A, Shamir R, Church GM: A global view of pleiotropy and phenotypically derived gene function in yeast. Mol Syst Biol 2005, 1:2005.0001.
  • [33]Hopkins AL: Network pharmacology. Nat Biotechnol 2007, 25(10):1110-1111.
  • [34]Hu G, Agarwal P: Human disease-drug network based on genomic expression profiles. Plos One 2009, 4(8):e6536.
  • [35]Hidalgo CA, Blumm N, Barabási A-L, Christakis NA: A dynamic network approach for the study of human phenotypes. PLoS Comp Biol 2009, 5(4):e1000353.
  • [36]Lee D-S, Park J, Kay K, Christakis N, Oltvai Z, Barabási A-L: The implications of human metabolic network topology for disease comorbidity. Proc Natl Acad Sci U S A 2008, 105(29):9880-9885.
  • [37]Paul M, Mehr AP, Kreutz R: Physiology of local renin-angiotensin systems. Physiol Rev 2006, 86(3):747-803.
  • [38]Lage K, Møllgård K, Greenway S, Wakimoto H, Gorham JM, Workman CT, Bendsen E, Hansen NT, Rigina O, Roque FS: Dissecting spatio-temporal protein networks driving human heart development and related disorders. Mol Syst Biol 2010, 6:381.
  • [39]Eldadah ZA, Hamosh A, Biery NJ, Montgomery RA, Duke M, Elkins R, Dietz HC: Familial Tetralogy of Fallot caused by mutation in the jagged1 gene. Hum Mol Genet 2001, 10(2):163-169.
  • [40]McElhinney DB, Krantz ID, Bason L, Piccoli DA, Emerick KM, Spinner NB, Goldmuntz E: Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome. Circulation 2002, 106(20):2567-2574.
  • [41]Winkler DT, Bondolfi L, Herzig MC, Jann L, Calhoun ME, Wiederhold KH, Tolnay M, Staufenbiel M, Jucker M: Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J Neurosci 2001, 21(5):1619-1627.
  • [42]Witt BJ, Ballman KV, Brown RD Jr, Meverden RA, Jacobsen SJ, Roger VL: The incidence of stroke after myocardial infarction: a meta-analysis. Am J Med 2006, 119(4):354. e1-354. e9.
  • [43]Mooe T, Eriksson P, Stegmayr B: Ischemic stroke after acute myocardial infarction a population-based study. Stroke 1997, 28(4):762-767.
  • [44]Pidoux G, Taskén K: Specificity and spatial dynamics of protein kinase A signaling organized by A-kinase-anchoring proteins. J Mol Endocrinol 2010, 44(5):271-284.
  • [45]Chen L, Marquardt ML, Tester DJ, Sampson KJ, Ackerman MJ, Kass RS: Mutation of an A-kinase-anchoring protein causes long-QT syndrome. Proc Natl Acad Sci U S A 2007, 104(52):20990-20995.
  • [46]Casey M, Vaughan CJ, He J, Hatcher CJ, Winter JM, Weremowicz S, Montgomery K, Kucherlapati R, Morton CC, Basson CT: Mutations in the protein kinase A R1α regulatory subunit cause familial cardiac myxomas and Carney complex. J Clin Invest 2000, 106(5):R31.
  • [47]Chan SY, White K, Loscalzo J: Deciphering the molecular basis of human cardiovascular disease through network biology. Curr Opin Cardiol 2012, 27(3):202.
  • [48]Lusis AJ, Weiss JN: Cardiovascular networks systems-based approaches to cardiovascular disease. Circulation 2010, 121(1):157-170.
  • [49]Besnard J, Ruda GF, Setola V, Abecassis K, Rodriguiz RM, Huang X-P, Norval S, Sassano MF, Shin AI, Webster LA: Automated design of ligands to polypharmacological profiles. Nature 2012, 492(7428):215-220.
  • [50]Zhou W, Huang C, Li Y, Duan J, Wang Y, Yang L: A systematic identification of multiple toxin–target interactions based on chemical, genomic and toxicological data. Toxicology 2013, 304:173-184.
  • [51]Zhu M, Gao L, Li X, Liu Z, Xu C, Yan Y, Walker E, Jiang W, Su B, Chen X: The analysis of the drug-targets based on the topological properties in the human protein-protein interaction network. J Drug Target 2009, 17(7):524-532.
  • [52]Bauer-Mehren A, Bundschus M, Rautschka M, Mayer MA, Sanz F, Furlong LI: Gene-disease network analysis reveals functional modules in mendelian, complex and environmental diseases. Plos One 2011, 6(6):e20284.
  • [53]Sieberts SK, Schadt EE: Moving toward a system genetics view of disease. Mamm Genome 2007, 18(6–7):389-401.
  • [54]Pujol A, Mosca R, Farrés J, Aloy P: Unveiling the role of network and systems biology in drug discovery. Trends Pharmacol Sci 2010, 31(3):115-123.
  • [55]Csermely P, Korcsmáros T, Kiss HJ, London G, Nussinov R: Structure and dynamics of molecular networks: A novel paradigm of drug discovery: A comprehensive review. Pharmacol Ther 2013, 138(3):333-408.
  • [56]MacLellan WR, Wang Y, Lusis AJ: Systems-based approaches to cardiovascular disease. Nat Rev Cardiol 2012, 9(3):172-184.
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