Effects of statin on circulating microRNAome and predicted function regulatory network in patients with unstable angina

BMC Medical Genomics

Ning Xu¹  Chengfu Cao²  Qiang Geng²  Sufang Li²  Chongyou Lee²  Jing Zhang²  Feng Zhang²  Junxian Song²  Jingyi Ren²  Hong Chen²  Jingjin Li² 

[1] Department of Medicine, Karolinska Institutet, Stockholm, Sweden;Department of Cardiology, Peking University People’s hospital, No. 11 Xizhimen South Street, Beijing 100044, China

关键词: Regulatory network;    System biology;    MicroRNA;    Statin;    Unstable angina;   

Others  :  1137787
DOI  :  10.1186/s12920-015-0082-4

 received in 2014-12-16, accepted in 2015-02-06,  发布年份 2015

【 摘 要 】

Background

Statin therapy plays a pivotal role in stabilizing the plaque for unstable angina (UA) patients although its mechanism(s) remains largely unexplored. Here we aim to identify microRNAs (miRNAs) mediating the protective effect of statins in UA patients.

Methods

MiRNAs Array was carried out to compare the circulating whole blood miRNA profile of UA patients treated with (n = 10) and without statin (n = 10) and plasma miRNA profile UA patients treated with (n = 5) and without statin (n = 5). 22 whole blood miRNAs and 19 plasma miRNAs were found significantly upregulated in statin group. Targets of these miRNAs were predicted by algoritms: Targetscan, Miranda and Diana microT, then clustered according to functions and cell types by using the Database for Annotation, Visualization and Integrated Discovery (DAVID). To reveal the enriched function pathways in human atherosclerotic plaque, we analyzed microarray data from GEO database, Coronary atherosclerotic plaque (n = 80); macrophages in ruptured plaque (n = 11); carotid atheroma plaque (n = 64); advanced carotid atherosclerotic plaque (n = 29) using Reactome database. Integrated analysis indicated that statin induced miRNAs mainly regulate the signaling pathways of Rho GTPase and hemostasis in human atherosclerotic lesion. In vulnerable plaque, additional immune system signaling was also targeted.

Results

The data showed target genes regulated by these statin induced miRNAs majorly expressed in i) plaque macrophage and platelet, where they were involved in hemostasis process; ii) in monocyte to regulate NGF apoptosis; iii) and in endothelial cell function in Rho GTPase pathway. Integrate analysis indicated that statin induced miRNAs mainly regulate the signaling pathways of Rho GTPase and hemostasis in human atherosclerotic lesion.

Conclusions

Our study suggest that statin induces the expression of multiple miRNAs in the circulation of UA patient, which play important roles by regulating signal pathways critical for the pathogenesis of UA.

【 授权许可】

   
2015 Li et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Sukhova GK, Williams JK, Libby P: Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol. Arterioscler Thromb Vasc Biol 2002, 22(9):1452-8.
• [2]Kleemann R, Princen HM, Emeis JJ, Jukema JW, Fontijn RD, Horrevoets AJ, et al.: Rosuvastatin reduces atherosclerosis development beyond and independent of its plasma cholesterol-lowering effect in APOE*3-Leiden transgenic mice: evidence for antiinflammatory effects of rosuvastatin. Circulation 2003, 108(11):1368-74.
• [3]Schneider MP, Schmidt BM, John S, Schmieder RE: Effects of statin treatment on endothelial function, oxidative stress and inflammation in patients with arterial hypertension and normal cholesterol levels. J Hypertens 2011, 29(9):1757-64.
• [4]Chen H, Ren JY, Xing Y, Zhang WL, Liu X, Wu P, et al.: Short-term withdrawal of simvastatin induces endothelial dysfunction in patients with coronary artery disease: a dose–response effect dependent on endothelial nitric oxide synthase. Int J Cardiol 2009, 131(3):313-20.
• [5]Takwi AA, Li Y, Becker Buscaglia LE, Zhang J, Choudhury S, Park AK, et al.: A statin-regulated microRNA represses human c-Myc expression and function. EMBO Mol Med 2012, 4(9):896-909.
• [6]Schober A, Nazari-Jahantigh M, Wei Y, Bidzhekov K, Gremse F, Grommes J, et al.: MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nat Med 2014, 20(4):368-76.
• [7]Sun X, He S, Wara AK, Icli B, Shvartz E, Tesmenitsky Y, et al.: Systemic delivery of microRNA-181b inhibits nuclear factor-kappaB activation, vascular inflammation, and atherosclerosis in apolipoprotein E-deficient mice. Circ Res 2014, 114(1):32-40.
• [8]Dentelli P, Rosso A, Orso F, Olgasi C, Taverna D, Brizzi MF: microRNA-222 controls neovascularization by regulating signal transducer and activator of transcription 5A expression. Arterioscler Thromb Vasc Biol 2010, 30(8):1562-8.
• [9]Dweep H, Sticht C, Pandey P, Gretz N: miRWalk--database: prediction of possible miRNA binding sites by “walking” the genes of three genomes. J Biomed Inform 2011, 44(5):839-47.
• [10]Friedman RC, Farh KK, Burge CB, Bartel DP: Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 2009, 19(1):92-105.
• [11]Betel D, Wilson M, Gabow A, Marks DS, Sander C: The microRNA.org resource: targets and expression. Nucleic Acids Res 2008, 36(Database issue):D149-53.
• [12]Maragkakis M, Reczko M, Simossis VA, Alexiou P, Papadopoulos GL, Dalamagas T, et al.: DIANA-microT web server: elucidating microRNA functions through target prediction. Nucleic Acids Res 2009, 37(Web Server issue):W273-6.
• [13]da Huang W, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009, 4(1):44-57.
• [14]Boon K, Osorio EC, Greenhut SF, Schaefer CF, Shoemaker J, Polyak K, et al.: An anatomy of normal and malignant gene expression. Proc Natl Acad Sci U S A 2002, 99(17):11287-92.
• [15]Croft D, Mundo AF, Haw R, Milacic M, Weiser J, Wu G, et al.: The Reactome pathway knowledgebase. Nucleic Acids Res 2014, 42(Database issue):D472-7.
• [16]Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al.: Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003, 13(11):2498-504.
• [17]Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, et al.: NCBI GEO: archive for functional genomics data sets–update. Nucleic Acids Res 2013, 41(Database issue):D991-5.
• [18]Hagg S, Skogsberg J, Lundstrom J, Noori P, Nilsson R, Zhong H, et al.: Multi-organ expression profiling uncovers a gene module in coronary artery disease involving transendothelial migration of leukocytes and LIM domain binding 2: the Stockholm Atherosclerosis Gene Expression (STAGE) study. PLoS Genet 2009, 5(12):e1000754.
• [19]Doring Y, Manthey HD, Drechsler M, Lievens D, Megens RT, Soehnlein O, et al.: Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis. Circulation 2012, 125(13):1673-83.
• [20]Ayari H, Bricca G: Identification of two genes potentially associated in iron-heme homeostasis in human carotid plaque using microarray analysis. J Biosci 2013, 38(2):311-5.
• [21]Bonauer A, Carmona G, Iwasaki M, Mione M, Koyanagi M, Fischer A, et al.: MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science 2009, 324(5935):1710-3.
• [22]Hua Z, Lv Q, Ye W, Wong CK, Cai G, Gu D, et al.: MiRNA-directed regulation of VEGF and other angiogenic factors under hypoxia. PLoS One 2006, 1:e116.
• [23]Asanome A, Kawabe J, Matsuki M, Kabara M, Hira Y, Bochimoto H, et al.: Nerve growth factor stimulates regeneration of perivascular nerve, and induces the maturation of microvessels around the injured artery. Biochem Biophys Res Commun 2014, 443(1):150-5.
• [24]Fiedler J, Jazbutyte V, Kirchmaier BC, Gupta SK, Lorenzen J, Hartmann D, et al.: MicroRNA-24 regulates vascularity after myocardial infarction. Circulation 2011, 124(6):720-30.
• [25]Hullinger TG, Montgomery RL, Seto AG, Dickinson BA, Semus HM, Lynch JM, et al.: Inhibition of miR-15 protects against cardiac ischemic injury. Circ Res 2012, 110(1):71-81.
• [26]Li C, Fang Z, Jiang T, Zhang Q, Liu C, Zhang C, et al.: Serum microRNAs profile from genome-wide serves as a fingerprint for diagnosis of acute myocardial infarction and angina pectoris. BMC Med Genomics 2013, 6:16. BioMed Central Full Text
• [27]Wang J, Pei Y, Zhong Y, Jiang S, Shao J, Gong J: Altered serum microRNAs as novel diagnostic biomarkers for atypical coronary artery disease. PLoS One 2014, 9(9):e107012.
• [28]Tanaka S, Fukumoto Y, Nochioka K, Minami T, Kudo S, Shiba N, et al.: Statins exert the pleiotropic effects through small GTP-binding protein dissociation stimulator upregulation with a resultant Rac1 degradation. Arterioscler Thromb Vasc Biol 2013, 33(7):1591-600.
• [29]Pastuszczak M, Kotlarz A, Mostowik M, Zalewski J, Zmudka K, Undas A: Prior simvastatin treatment is associated with reduced thrombin generation and platelet activation in patients with acute ST-segment elevation myocardial infarction. Thromb Res 2010, 125(5):382-6.
• [30]Mathers CD, Loncar D: Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006, 3(11):e442.
• [31]Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al.: A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009, 360(18):1851-61.
• [32]Hulten E, Jackson JL, Douglas K, George S, Villines TC: The effect of early, intensive statin therapy on acute coronary syndrome: a meta-analysis of randomized controlled trials. Arch Intern Med 2006, 166(17):1814-21.
• [33]Laufs U, Gertz K, Huang P, Nickenig G, Bohm M, Dirnagl U, et al.: Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice. Stroke 2000, 31(10):2442-9.
• [34]Haramaki N, Ikeda H, Takenaka K, Katoh A, Sugano R, Yamagishi S, et al.: Fluvastatin alters platelet aggregability in patients with hypercholesterolemia: possible improvement of intraplatelet redox imbalance via HMG-CoA reductase. Arterioscler Thromb Vasc Biol 2007, 27(6):1471-7.
• [35]Aikawa M, Rabkin E, Sugiyama S, Voglic SJ, Fukumoto Y, Furukawa Y, et al.: An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation 2001, 103(2):276-83.
• [36]Kandabashi T, Shimokawa H, Miyata K, Kunihiro I, Kawano Y, Fukata Y, et al.: Inhibition of myosin phosphatase by upregulated rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1beta. Circulation 2000, 101(11):1319-23.
• [37]Kandabashi T, Shimokawa H, Mukai Y, Matoba T, Kunihiro I, Morikawa K, et al.: Involvement of rho-kinase in agonists-induced contractions of arteriosclerotic human arteries. Arterioscler Thromb Vasc Biol 2002, 22(2):243-8.
• [38]Mallat Z, Gojova A, Sauzeau V, Brun V, Silvestre JS, Esposito B, et al.: Rho-associated protein kinase contributes to early atherosclerotic lesion formation in mice. Circ Res 2003, 93(9):884-8.
• [39]Morishige K, Shimokawa H, Eto Y, Kandabashi T, Miyata K, Matsumoto Y, et al.: Adenovirus-mediated transfer of dominant-negative rho-kinase induces a regression of coronary arteriosclerosis in pigs in vivo. Arterioscler Thromb Vasc Biol 2001, 21(4):548-54.
• [40]Fox R, Nhan TQ, Law GL, Morris DR, Liles WC, Schwartz SM: PSGL-1 and mTOR regulate translation of ROCK-1 and physiological functions of macrophages. EMBO J 2007, 26(2):505-15.
• [41]Chen H, Ikeda U, Shimpo M, Ikeda M, Minota S, Shimada K: Fluvastatin upregulates inducible nitric oxide synthase expression in cytokine-stimulated vascular smooth muscle cells. Hypertension 2000, 36(6):923-8.
• [42]Cicha I, Schneiderhan-Marra N, Yilmaz A, Garlichs CD, Goppelt-Struebe M: Monitoring the cellular effects of HMG-CoA reductase inhibitors in vitro and ex vivo. Arterioscler Thromb Vasc Biol 2004, 24(11):2046-50.
• [43]Chaldakov GN, Fiore M, Stankulov IS, Hristova M, Antonelli A, Manni L, et al.: NGF, BDNF, leptin, and mast cells in human coronary atherosclerosis and metabolic syndrome. Arch Physiol Biochem 2001, 109(4):357-60.
• [44]Manni L, Nikolova V, Vyagova D, Chaldakov GN, Aloe L: Reduced plasma levels of NGF and BDNF in patients with acute coronary syndromes. Int J Cardiol 2005, 102(1):169-71.