MicroRNA in cardiovascular aging and age-related cardiovascular diseases

Frontiers of Medicine

Volumn 4, Issue , 2017, Pages

  De Lucia, Claudio ^a,b   Komici, Klara ^a   Borghetti, Giulia ^b   Femminella, Grazia Daniela ^a   Bencivenga, Leonardo ^a   Cannavo, Alessandro ^a,b   Corbi, Graziamaria ^c   Ferrara, Nicola ^a,d   Houser, Steven R ^b   Koch, Walter J ^b   Rengo, Giuseppe ^a,d  

^a UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^b TEMPLE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c UNIVERSITY OF MOLISE   (Italy)

^d IRCCS   (Italy)

Author keywords

Aging; Atherosclerosis; Atrial fibrillation; Cardiovascular diseases; Diabetes; Heart failure; Hypertension; MicroRNA

Indexed keywords

EID: 85041687585     PISSN: 20950217     EISSN: 20950225     Source Type: Journal    
DOI: 10.3389/fmed.2017.00074     Document Type: Review

References (263)

1. Niccoli T, Partridge L. Ageing as a risk factor for disease. Curr Biol (2012) 22(17):R741-52. doi:10.1016/j.cub.2012.07.024
2. North BJ, Sinclair DA. The intersection between aging and cardio-vascular disease. Circ Res (2012) 110(8):1097-108. doi:10.1161/CIRCRESAHA.111.246876
3. Ahto M, Isoaho R, Puolijoki H, Laippala P, Romo M, Kivelä SL. Functional abilities of elderly coronary heart disease patients. Aging (Milano) (1998) 10(2):127-36.
4. Dai DF, Chen T, Johnson SC, Szeto H, Rabinovitch PS. Cardiac aging: from molecular mechanisms to significance in human health and disease. Antioxid Redox Signal (2012) 16(12):1492-526. doi:10.1089/ars.2011.4179
5. Boyle AJ, Shih H, Hwang J, Ye J, Lee B, Zhang Y, et al. Cardiomyopathy of aging in the mammalian heart is characterized by myocardial hypertrophy, fibrosis and a predisposition towards cardiomyocyte apoptosis and autoph-agy. Exp Gerontol (2011) 46(7):549-59. doi:10.1016/j.exger.2011.02.010
6. Strait JB, Lakatta EG. Aging-associated cardiovascular changes and their rela-tionship to heart failure. Heart Fail Clin (2012) 8(1):143-64. doi:10.1016/j.hfc.2011.08.011
7. Rengo G, Pagano G, Vitale DF, Formisano R, Komici K, Petraglia L, et al. Impact of aging on cardiac sympathetic innervation measured by (123) I-mIBG imaging in patients with systolic heart failure. Eur J Nucl Med Mol Imaging (2016) 43(13):2392-400. doi:10.1007/s00259-016-3432-3
8. Ungvari Z, Kaley G, de Cabo R, Sonntag WE, Csiszar A. Mechanisms of vascular aging: new perspectives. J Gerontol A Biol Sci Med Sci (2010) 65(10):1028-41. doi:10.1093/gerona/glq113
9. Csiszar A, Ungvari Z, Edwards JG, Kaminski P, Wolin MS, Koller A, et al. Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar func-tion. Circ Res (2002) 90(11):1159-66. doi:10.1161/01.RES.0000020401.61826.EA
10. Ungvari Z, Buffenstein R, Austad SN, Podlutsky A, Kaley G, Csiszar A. Oxidative stress in vascular senescence: lessons from successfully aging species. Front Biosci (2008) 13:5056-70. doi:10.2741/3064
11. Lin CC, Chang YM, Pan CT, Chen CC, Ling L, Tsao KC, et al. Functional evolution of cardiac microRNAs in heart development and functions. Mol Biol Evol (2014) 31(10):2722-34. doi:10.1093/molbev/msu217
12. Altuvia Y, Landgraf P, Lithwick G, Elefant N, Pfeffer S, Aravin A, et al. Clustering and conservation patterns of human microRNAs. Nucleic Acids Res (2005) 33(8):2697-706. doi:10.1093/nar/gki567
13. Daugaard I, Hansen TB. Biogenesis and function of Ago-associated RNAs. Trends Genet (2017) 33(3):208-19. doi:10.1016/j.tig.2017.01.003
14. Fazi F, Nervi C. microRNA: basic mechanisms and transcriptional regulatory networks for cell fate determination. Cardiovasc Res (2008) 79(4):553-61. doi:10.1093/cvr/cvn151
15. Borchert GM, Lanier W, Davidson BL. RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol (2006) 13(12):1097-101. doi:10.1038/nsmb1167
16. Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, et al. The nuclear RNase III Drosha initiates microRNA processing. Nature (2003) 425(6956):415-9. doi:10.1038/nature01957
17. Thomas M, Lieberman J, Lal A. Desperately seeking microRNA targets. Nat Struct Mol Biol (2010) 17(10):1169-74. doi:10.1038/nsmb.1921
18. Lytle JR, Yario TA, Steitz JA. Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proc Natl Acad Sci U S A (2007) 104(23):9667-72. doi:10.1073/pnas.0703820104
19. Bartel DP. microRNAs: genomics, biogenesis, mechanism, and function. Cell (2004) 116(2):281-97. doi:10.1016/S0092-8674(04)00045-5
20. Ambros V, Bartel B, Bartel DP, Burge CB, Carrington JC, Chen X, et al. A uni-form system for microRNA annotation. RNA (2003) 9(3):277-9. doi:10.1261/rna.2183803
21. Griffiths-Jones S. The microRNA registry. Nucleic Acids Res (2004) 32 (Database issue):D109-11. doi:10.1093/nar/gkh023
22. Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ. miR-Base: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res (2006) 34(Database issue):D140-4. doi:10.1093/nar/gkj112
23. Budak H, Bulut R, Kantar M, Alptekin B. microRNA nomenclature and the need for a revised naming prescription. Brief Funct Genomics (2016) 15(1):65-71. doi:10.1093/bfgp/elv026
24. Bronze-da-Rocha E. microRNAs expression profiles in cardiovascular diseases. Biomed Res Int (2014) 2014:985408. doi:10.1155/2014/985408
25. Wang GK, Zhu JQ, Zhang JT, Li Q, Li Y, He J, et al. Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. Eur Heart J (2010) 31(6):659-66. doi:10.1093/eurheartj/ehq013
26. Endzeliņš E, Melne V, Kalniņa Z, Lietuvietis V, Riekstiņa U, Llorente A, et al. Diagnostic, prognostic and predictive value of cell-free miRNAs in prostate cancer: a systematic review. Mol Cancer (2016) 15(1):41. doi:10.1186/s12943-016-0523-5
27. Tijsen AJ, Pinto YM, Creemers EE. Circulating microRNAs as diagnostic biomarkers for cardiovascular diseases. Am J Physiol Heart Circ Physiol (2012) 303(9):H1085-95. doi:10.1152/ajpheart.00191.2012
28. Li C, Pei F, Zhu X, Duan DD, Zeng C. Circulating microRNAs as novel and sensitive biomarkers of acute myocardial infarction. Clin Biochem (2012) 45(10-11):727-32. doi:10.1016/j.clinbiochem.2012.04.013
29. Viereck J, Thum T. Circulating noncoding RNAs as biomarkers of cardio-vascular disease and injury. Circ Res (2017) 120(2):381-99. doi:10.1161/CIRCRESAHA.116.308434
30. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A (2008) 105(30):10513-8. doi:10.1073/pnas.0804549105
31. Turchinovich A, Weiz L, Langheinz A, Burwinkel B. Characterization of extracellular circulating microRNA. Nucleic Acids Res (2011) 39(16):7223-33. doi:10.1093/nar/gkr254
32. Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF, et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A (2011) 108(12):5003-8. doi:10.1073/pnas.1019055108
33. Turchinovich A, Weiz L, Burwinkel B. Extracellular miRNAs: the mystery of their origin and function. Trends Biochem Sci (2012) 37(11):460-5. doi:10.1016/j.tibs.2012.08.003
34. Turchinovich A, Samatov TR, Tonevitsky AG, Burwinkel B. Circulating miRNAs: cell-cell communication function? Front Genet (2013) 4:119. doi:10.3389/fgene.2013.00119
35. Théry C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol (2009) 9(8):581-93. doi:10.1038/nri2567
36. Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol (2014) 30:255-89. doi:10.1146/annurev-cellbio-101512-122326
37. Yáñez-Mó M, Siljander PR, Andreu Z, Zavec AB, Borràs FE, Buzas EI, et al. Biological properties of extracellular vesicles and their physiological func-tions. J Extracell Vesicles (2015) 4:27066. doi:10.3402/jev.v4.27066
38. Kalra H, Simpson RJ, Ji H, Aikawa E, Altevogt P, Askenase P, et al. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol (2012) 10(12):e1001450. doi:10.1371/journal.pbio.1001450
39. Atkin-Smith GK, Tixeira R, Paone S, Mathivanan S, Collins C, Liem M, et al. A novel mechanism of generating extracellular vesicles during apoptosis via a beads-on-a-string membrane structure. Nat Commun (2015) 6:7439. doi:10.1038/ncomms8439
40. Lv Z, Wei Y, Wang D, Zhang CY, Zen K, Li L. Argonaute 2 in cell-secreted microvesicles guides the function of secreted miRNAs in recipient cells. PLoS One (2014) 9(7):e103599. doi:10.1371/journal.pone.0103599
41. Biglino G, Caputo M, Rajakaruna C, Angelini G, van Rooij E, Emanueli C. Modulating microRNAs in cardiac surgery patients: novel therapeutic opportunities? Pharmacol Ther (2017) 170:192-204. doi:10.1016/j.pharmthera.2016.11.004
42. Fasanaro P, Greco S, Ivan M, Capogrossi MC, Martelli F. microRNA: emerg-ing therapeutic targets in acute ischemic diseases. Pharmacol Ther (2010) 125(1):92-104. doi:10.1016/j.pharmthera.2009.10.003
43. Ling H, Fabbri M, Calin GA. microRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov (2013) 12(11):847-65. doi:10.1038/nrd4140
44. Weiler J, Hunziker J, Hall J. Anti-miRNA oligonucleotides (AMOs): ammu-nition to target miRNAs implicated in human disease? Gene Ther (2006) 13(6):496-502. doi:10.1038/sj.gt.3302654
45. Lesizza P, Prosdocimo G, Martinelli V, Sinagra G, Zacchigna S, Giacca M. Single-dose intracardiac injection of pro-regenerative microRNAs improves cardiac function after myocardial infarction. Circ Res (2017) 120(8):1298-304. doi:10.1161/CIRCRESAHA.116.309589
46. Bellera N, Barba I, Rodriguez-Sinovas A, Ferret E, Asín MA, Gonzalez-Alujas MT, et al. Single intracoronary injection of encapsulated antago-mir-92a promotes angiogenesis and prevents adverse infarct remodeling. J Am Heart Assoc (2014) 3(5):e000946. doi:10.1161/JAHA.114.000946
47. Schäfer F, Wagner J, Knau A, Dimmeler S, Heckel A. Regulating angiogen-esis with light-inducible antimiRs. Angew Chem Int Ed Engl (2013) 52(51): 13558-61. doi:10.1002/anie.201307502
48. Hastings CL, Roche ET, Ruiz-Hernandez E, Schenke-Layland K, Walsh CJ, Duffy GP. Drug and cell delivery for cardiac regeneration. Adv Drug Deliv Rev (2015) 84:85-106. doi:10.1016/j.addr.2014.08.006
49. Zhang X, Azhar G, Williams ED, Rogers SC, Wei JY. microRNA clusters in the adult mouse heart: age-associated changes. Biomed Res Int (2015) 2015:732397. doi:10.1155/2015/732397
50. Zhang X, Azhar G, Wei JY. The expression of microRNA and microRNA clusters in the aging heart. PLoS One (2012) 7(4):e34688. doi:10.1371/journal.pone.0034688
51. Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, et al. microRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature (2008) 456(7224):980-4. doi:10.1038/nature07511
52. Jazbutyte V, Fiedler J, Kneitz S, Galuppo P, Just A, Holzmann A, et al. microRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart. Age (Dordr) (2013) 35(3):747-62. doi:10.1007/s11357-012-9407-9
53. Kampmann A, Fernández B, Deindl E, Kubin T, Pipp F, Eitenmüller I, et al. The proteoglycan osteoglycin/mimecan is correlated with arteriogenesis. Mol Cell Biochem (2009) 322(1-2):15-23. doi:10.1007/s11010-008-9935-x
54. Iozzo RV. The family of the small leucine-rich proteoglycans: key regulators of matrix assembly and cellular growth. Crit Rev Biochem Mol Biol (1997) 32(2):141-74. doi:10.3109/10409239709108551
55. Tasheva ES, Koester A, Paulsen AQ, Garrett AS, Boyle DL, Davidson HJ, et al. Mimecan/osteoglycin-deficient mice have collagen fibril abnormalities. Mol Vis (2002) 8:407-15.
56. Gupta SK, Foinquinos A, Thum S, Remke J, Zimmer K, Bauters C, et al. Preclinical development of a microRNA-based therapy for elderly patients with myocardial infarction. J Am Coll Cardiol (2016) 68(14):1557-71. doi:10.1016/j.jacc.2016.07.739
57. Dimitrakopoulou K, Vrahatis AG, Bezerianos A. Integromics network meta-analysis on cardiac aging offers robust multi-layer modular signa-tures and reveals micronome synergism. BMC Genomics (2015) 16:147. doi:10.1186/s12864-015-1256-3
58. van Almen GC, Verhesen W, van Leeuwen RE, van de Vrie M, Eurlings C, Schellings MW, et al. microRNA-18 and microRNA-19 regulate CTGF and TSP-1 expression in age-related heart failure. Aging Cell (2011) 10(5):769-79. doi:10.1111/j.1474-9726.2011.00714.x
59. Zhou M, Cai J, Tang Y, Zhao Q. miR-17-92 cluster is a novel regulatory gene of cardiac ischemic/reperfusion injury. Med Hypotheses (2013) 81(1):108-10. doi:10.1016/j.mehy.2013.03.043
60. Bader F, Atallah B, Brennan LF, Rimawi RH, Khalil ME. Heart failure in the elderly: ten peculiar management considerations. Heart Fail Rev (2017) 22(2):219-28. doi:10.1007/s10741-017-9598-3
61. Du WW, Li X, Li T, Li H, Khorshidi A, Liu F, et al. The microRNA miR-17-3p inhibits mouse cardiac fibroblast senescence by targeting Par4. J Cell Sci (2015) 128(2):293-304. doi:10.1242/jcs.158360
62. Boon RA, Iekushi K, Lechner S, Seeger T, Fischer A, Heydt S, et al. microR-NA-34a regulates cardiac ageing and function. Nature (2013) 495(7439): 107-10. doi:10.1038/nature11919
63. AlGhatrif M, Lakatta EG. The conundrum of arterial stiffness, elevated blood pressure, and aging. Curr Hypertens Rep (2015) 17(2):12. doi:10.1007/s11906-014-0523-z
64. Camici GG, Savarese G, Akhmedov A, Lüscher TF. Molecular mechanism of endothelial and vascular aging: implications for cardiovascular disease. Eur Heart J (2015) 36(48):3392-403. doi:10.1093/eurheartj/ehv587
65. Sun Z. Aging, arterial stiffness, and hypertension. Hypertension (2015) 65(2):252-6. doi:10.1161/HYPERTENSIONAHA.114.03617
66. Marigliano V, Scuteri A, Cacciafesta M, Bellucci CR, Di Bernardo MG, De Propris AM, et al. Hypertension and atherosclerosis in the elderly: pathoge-netic common mechanism and intervention strategies. Clin Exp Hypertens (1993) 15(Suppl 1):9-29.
67. Kaess BM, Rong J, Larson MG, Hamburg NM, Vita JA, Levy D, et al. Aortic stiffness, blood pressure progression, and incident hypertension. JAMA (2012) 308(9):875-81. doi:10.1001/2012.jama.10503
68. Ito T, Yagi S, Yamakuchi M. microRNA-34a regulation of endothelial senes-cence. Biochem Biophys Res Commun (2010) 398(4):735-40. doi:10.1016/j.bbrc.2010.07.012
69. Tabuchi T, Satoh M, Itoh T, Nakamura M. microRNA-34a regulates the longevity-associated protein SIRT1 in coronary artery disease: effect of statins on SIRT1 and microRNA-34a expression. Clin Sci (Lond) (2012) 123(3):161-71. doi:10.1042/CS20110563
70. Xu Q, Seeger FH, Castillo J, Iekushi K, Boon RA, Farcas R, et al. micro-RNA-34a contributes to the impaired function of bone marrow-derived mononu-clear cells from patients with cardiovascular disease. J Am Coll Cardiol (2012) 59(23):2107-17. doi:10.1016/j.jacc.2012.02.033
71. Badi I, Burba I, Ruggeri C, Zeni F, Bertolotti M, Scopece A, et al. microR-NA-34a induces vascular smooth muscle cells senescence by SIRT1 down-regulation and promotes the expression of age-associated pro-inflammatory secretory factors. J Gerontol A Biol Sci Med Sci (2015) 70(11):1304-11. doi:10.1093/gerona/glu180
72. Guarani V, Deflorian G, Franco CA, Krüger M, Phng LK, Bentley K, et al. Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase. Nature (2011) 473(7346):234-8. doi:10.1038/nature09917
73. Menghini R, Casagrande V, Cardellini M, Martelli E, Terrinoni A, Amati F, et al. microRNA 217 modulates endothelial cell senescence via silent information regulator 1. Circulation (2009) 120(15):1524-32. doi:10.1161/CIRCULATIONAHA.109.864629
74. Boon RA, Seeger T, Heydt S, Fischer A, Hergenreider E, Horrevoets AJ, et al. microRNA-29 in aortic dilation: implications for aneurysm formation. Circ Res (2011) 109(10):1115-9. doi:10.1161/CIRCRESAHA.111.255737
75. Boon RA, Dimmeler S. microRNAs and aneurysm formation. Trends Cardiovasc Med (2011) 21(6):172-7. doi:10.1016/j.tcm.2012.05.005
76. Merk DR, Chin JT, Dake BA, Maegdefessel L, Miller MO, Kimura N, et al. miR-29b participates in early aneurysm development in Marfan syndrome. Circ Res (2012) 110(2):312-24. doi:10.1161/CIRCRESAHA.111.253740
77. Maegdefessel L, Azuma J, Toh R, Merk DR, Deng A, Chin JT, et al. Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development. J Clin Invest (2012) 122(2):497-506. doi:10.1172/JCI61598
78. Vasa-Nicotera M, Chen H, Tucci P, Yang AL, Saintigny G, Menghini R, et al. miR-146a is modulated in human endothelial cell with aging. Atherosclerosis (2011) 217(2):326-30. doi:10.1016/j.atherosclerosis.2011.03.034
79. Olivieri F, Lazzarini R, Recchioni R, Marcheselli F, Rippo MR, Di Nuzzo S, et al. miR-146a as marker of senescence-associated pro-inflammatory status in cells involved in vascular remodelling. Age (Dordr) (2013) 35(4):1157-72. doi:10.1007/s11357-012-9440-8
80. Hazra S, Henson GD, Morgan RG, Breevoort SR, Ives SJ, Richardson RS, et al. Experimental reduction of miR-92a mimics arterial aging. Exp Gerontol (2016) 83:165-70. doi:10.1016/j.exger.2016.08.007
81. Wieland D, Ferrucci L. Multidimensional geriatric assessment: back to the future. J Gerontol A Biol Sci Med Sci (2008) 63(3):272-4. doi:10.1093/gerona/63.3.272
82. Rengo F, Parisi V, Rengo G, Femminella GD, Rengo C, Zincarelli C, et al. Instruments for geriatric assessment: new multidimensional assessment approaches. J Nephrol (2012) 25(Suppl 19):S73-8. doi:10.5301/jn.5000164
83. Pilotto A, Cella A, Daragjati J, Veronese N, Musacchio C, Mello AM, et al. Three decades of comprehensive geriatric assessment: evidence coming from different healthcare settings and specific clinical conditions. J Am Med Dir Assoc (2017) 18(2):192.e1-11. doi:10.1016/j.jamda.2016.11.004
84. Dent E, Kowal P, Hoogendijk EO. Frailty measurement in research and clinical practice: a review. Eur J Intern Med (2016) 31:3-10. doi:10.1016/j.ejim.2016.03.007
85. Rockwood K, Song X, MacKnight C, Bergman H, Hogan DB, McDowell I, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ (2005) 173(5):489-95. doi:10.1503/cmaj.050051
86. Pilotto A, Addante F, Franceschi M, Leandro G, Rengo G, D’Ambrosio P, et al. Multidimensional prognostic index based on a comprehensive geriatric assessment predicts short-term mortality in older patients with heart failure. Circ Heart Fail (2010) 3(1):14-20. doi:10.1161/CIRCHEARTFAILURE.109.865022
87. Giantin V, Falci C, De Luca E, Valentini E, Iasevoli M, Siviero P, et al. Performance of the multidimensional geriatric assessment and multidimen-sional prognostic index in predicting negative outcomes in older adults with cancer. Eur J Cancer Care (Engl) (2016). doi:10.1111/ecc.12585
88. Victoria B, Dhahbi JM, Nunez Lopez YO, Spinel L, Atamna H, Spindler SR, et al. Circulating microRNA signature of genotype-by-age interactions in the long-lived Ames dwarf mouse. Aging Cell (2015) 14(6):1055-66. doi:10.1111/acel.12373
89. Victoria B, Nunez Lopez YO, Masternak MM. microRNAs and the metabolic hallmarks of aging. Mol Cell Endocrinol (2017). doi:10.1016/j.mce.2016.12.021
90. Olivieri F, Capri M, Bonafè M, Morsiani C, Jung HJ, Spazzafumo L, et al. Circulating miRNAs and miRNA shuttles as biomarkers: perspective trajec-tories of healthy and unhealthy aging. Mech Ageing Dev (2016). doi:10.1016/j.mad.2016.12.004
91. Zovoilis A, Agbemenyah HY, Agis-Balboa RC, Stilling RM, Edbauer D, Rao P, et al. microRNA-34c is a novel target to treat dementias. EMBO J (2011) 30(20):4299-308. doi:10.1038/emboj.2011.327
92. Bernardo BC, Gao XM, Winbanks CE, Boey EJ, Tham YK, Kiriazis H, et al. Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function. Proc Natl Acad Sci U S A (2012) 109(43):17615-20. doi:10.1073/pnas.1206432109
93. Serna E, Gambini J, Borras C, Abdelaziz KM, Mohammed K, Belenguer A, et al. Centenarians, but not octogenarians, up-regulate the expression of microRNAs. Sci Rep (2012) 2:961. doi:10.1038/srep00961
94. Olivieri F, Spazzafumo L, Santini G, Lazzarini R, Albertini MC, Rippo MR, et al. Age-related differences in the expression of circulating microRNAs: miR-21 as a new circulating marker of inflammaging. Mech Ageing Dev (2012) 133(11-12):675-85. doi:10.1016/j.mad.2012.09.004
95. Olivieri F, Bonafè M, Spazzafumo L, Gobbi M, Prattichizzo F, Recchioni R, et al. Age-and glycemia-related miR-126-3p levels in plasma and endothelial cells. Aging (Albany NY) (2014) 6(9):771-87. doi:10.18632/aging.100693
96. Ameling S, Kacprowski T, Chilukoti RK, Malsch C, Liebscher V, Suhre K, et al. Associations of circulating plasma microRNAs with age, body mass index and sex in a population-based study. BMC Med Genomics (2015) 8:61. doi:10.1186/s12920-015-0136-7
97. Zhang Y, Liu YJ, Liu T, Zhang H, Yang SJ. Plasma microRNA-21 is a potential diagnostic biomarker of acute myocardial infarction. Eur Rev Med Pharmacol Sci (2016) 20(2):323-9.
98. Gao Y, Dai M, Liu H, He W, Lin S, Yuan T, et al. Diagnostic value of circulating miR-21: an update meta-analysis in various cancers and validation in endometrial cancer. Oncotarget (2016) 7(42):68894-908. doi:10.18632/oncotarget.12028
99. Seeger T, Haffez F, Fischer A, Koehl U, Leistner DM, Seeger FH, et al. Immunosenescence-associated microRNAs in age and heart failure. Eur J Heart Fail (2013) 15(4):385-93. doi:10.1093/eurjhf/hfs184
100. Ferrara N, Komici K, Corbi G, Pagano G, Furgi G, Rengo C, et al. β-adrenergic receptor responsiveness in aging heart and clinical implications. Front Physiol (2014) 4:396. doi:10.3389/fphys.2013.00396
101. Lymperopoulos A, Rengo G, Koch WJ. Adrenergic nervous system in heart failure: pathophysiology and therapy. Circ Res (2013) 113(6):739-53. doi:10.1161/CIRCRESAHA.113.300308
102. Rengo G, Lymperopoulos A, Koch WJ. Future G protein-coupled receptor targets for treatment of heart failure. Curr Treat Options Cardiovasc Med (2009) 11(4):328-38. doi:10.1007/s11936-009-0033-5
103. de Lucia C, Femminella GD, Gambino G, Pagano G, Allocca E, Rengo C, et al. Adrenal adrenoceptors in heart failure. Front Physiol (2014) 5:246. doi:10.3389/fphys.2014.00246
104. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation (2016) 133(4):e38-360. doi:10.1161/CIR.0000000000000350
105. Deng J, Zhong Q. Advanced research on the microRNA mechanism in heart failure. Int J Cardiol (2016) 220:61-4. doi:10.1016/j.ijcard.2016.06.185
106. Wang J, Liew OW, Richards AM, Chen YT. Overview of microRNAs in cardiac hypertrophy, fibrosis, and apoptosis. Int J Mol Sci (2016) 17(5):E749. doi:10.3390/ijms17050749
107. Zhao Y, Samal E, Srivastava D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature (2005) 436(7048):214-20. doi:10.1038/nature03817
108. Sayed D, Hong C, Chen IY, Lypowy J, Abdellatif M. microRNAs play an essential role in the development of cardiac hypertrophy. Circ Res (2007) 100(3):416-24. doi:10.1161/01.RES.0000257913.42552.23
109. Ghosh AK, Nagpal V, Covington JW, Michaels MA, Vaughan DE. Molecular basis of cardiac endothelial-to-mesenchymal transition (EndMT): differential expression of microRNAs during EndMT. Cell Signal (2012) 24(5):1031-6. doi:10.1016/j.cellsig.2011.12.024
110. Elia L, Contu R, Quintavalle M, Varrone F, Chimenti C, Russo MA, et al. Reciprocal regulation of microRNA-1 and insulin-like growth factor-1 signal transduction cascade in cardiac and skeletal muscle in physiological and pathological conditions. Circulation (2009) 120(23):2377-85. doi:10.1161/CIRCULATIONAHA.109.879429
111. Melman YF, Shah R, Das S. microRNAs in heart failure: is the picture becoming less miRky? Circ Heart Fail (2014) 7(1):203-14. doi:10.1161/CIRCHEARTFAILURE.113.000266
112. Carè A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P, et al. microRNA-133 controls cardiac hypertrophy. Nat Med (2007) 13(5):613-8. doi:10.1038/nm1582
113. Li Q, Lin X, Yang X, Chang J. NFATc4 is negatively regulated in miR-133a-mediated cardiomyocyte hypertrophic repression. Am J Physiol Heart Circ Physiol (2010) 298(5):H1340-7. doi:10.1152/ajpheart.00592.2009
114. Nagalingam RS, Sundaresan NR, Gupta MP, Geenen DL, Solaro RJ, Gupta M. A cardiac-enriched microRNA, miR-378, blocks cardiac hyper-trophy by targeting Ras signaling. J Biol Chem (2013) 288(16):11216-32. doi:10.1074/jbc.M112.442384
115. Xu XD, Song XW, Li Q, Wang GK, Jing Q, Qin YW. Attenuation of microRNA-22 derepressed PTEN to effectively protect rat cardiomyocytes from hypertrophy. J Cell Physiol (2012) 227(4):1391-8. doi:10.1002/jcp.22852
116. Wang J, Song Y, Zhang Y, Xiao H, Sun Q, Hou N, et al. Cardiomyocyte overexpression of miR-27b induces cardiac hypertrophy and dysfunction in mice. Cell Res (2012) 22(3):516-27. doi:10.1038/cr.2011.132
117. Wang K, Lin ZQ, Long B, Li JH, Zhou J, Li PF. Cardiac hypertrophy is posi-tively regulated by microRNA miR-23a. J Biol Chem (2012) 287(1):589-99. doi:10.1074/jbc.M111.266940
118. Ucar A, Gupta SK, Fiedler J, Erikci E, Kardasinski M, Batkai S, et al. The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyo-cyte autophagy. Nat Commun (2012) 3:1078. doi:10.1038/ncomms2090
119. Callis TE, Pandya K, Seok HY, Tang RH, Tatsuguchi M, Huang ZP, et al. microRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. J Clin Invest (2009) 119(9):2772-86. doi:10.1172/JCI36154
120. Sucharov CC, Kao DP, Port JD, Karimpour-Fard A, Quaife RA, Minobe W, et al. Myocardial microRNAs associated with reverse remodeling in human heart failure. JCI Insight (2017) 2(2):e89169. doi:10.1172/jci.insight.89169
121. Wei C, Li L, Kim IK, Sun P, Gupta S. NF-κB mediated miR-21 regulation in cardiomyocytes apoptosis under oxidative stress. Free Radic Res (2014) 48(3):282-91. doi:10.3109/10715762.2013.865839
122. Yang Q, Yang K, Li A. microRNA-21 protects against ischemia-reperfusion and hypoxia-reperfusion-induced cardiocyte apoptosis via the phosphatase and tensin homolog/Akt-dependent mechanism. Mol Med Rep (2014) 9(6):2213-20. doi:10.3892/mmr.2014.2068
123. Li J, Donath S, Li Y, Qin D, Prabhakar BS, Li P. miR-30 regulates mitochondrial fission through targeting p53 and the dynamin-related protein-1 pathway. PLoS Genet (2010) 6(1):e1000795. doi:10.1371/journal.pgen.1000795
124. Roca-Alonso L, Castellano L, Mills A, Dabrowska AF, Sikkel MB, Pellegrino L, et al. Myocardial miR-30 downregulation triggered by doxo-rubicin drives alterations in β-adrenergic signaling and enhances apoptosis. Cell Death Dis (2015) 6:e1754. doi:10.1038/cddis.2015.89
125. Rane S, He M, Sayed D, Vashistha H, Malhotra A, Sadoshima J, et al. Downregulation of miR-199a derepresses hypoxia-inducible factor-1alpha and sirtuin 1 and recapitulates hypoxia preconditioning in cardiac myocytes. Circ Res (2009) 104(7):879-86. doi:10.1161/CIRCRESAHA.108.193102
126. Pan Z, Sun X, Ren J, Li X, Gao X, Lu C, et al. miR-1 exacerbates cardiac ischemia-reperfusion injury in mouse models. PLoS One (2012) 7(11):e50515. doi:10.1371/journal.pone.0050515
127. Ren XP, Wu J, Wang X, Sartor MA, Qian J, Jones K, et al. microRNA-320 is involved in the regulation of cardiac ischemia/reperfusion injury by targeting heat-shock protein 20. Circulation (2009) 119(17):2357-66. doi:10.1161/CIRCULATIONAHA.108.814145
128. Liu L, Zhang G, Liang Z, Liu X, Li T, Fan J, et al. microRNA-15b enhances hypoxia/reoxygenation-induced apoptosis of cardiomyocytes via a mito-chondrial apoptotic pathway. Apoptosis (2014) 19(1):19-29. doi:10.1007/s10495-013-0899-2
129. Zhang B, Zhou M, Li C, Zhou J, Li H, Zhu D, et al. microRNA-92a inhi-bition attenuates hypoxia/reoxygenation-induced myocardiocyte apoptosis by targeting Smad7. PLoS One (2014) 9(6):e100298. doi:10.1371/journal.pone.0100298
130. Roy S, Khanna S, Hussain SR, Biswas S, Azad A, Rink C, et al. microRNA expression in response to murine myocardial infarction: miR-21 regulates fibroblast metalloprotease-2 via phosphatase and tensin homologue. Cardiovasc Res (2009) 82(1):21-9. doi:10.1093/cvr/cvp015
131. Villar AV, García R, Merino D, Llano M, Cobo M, Montalvo C, et al. Myocardial and circulating levels of microRNA-21 reflect left ventricular fibrosis in aortic stenosis patients. Int J Cardiol (2013) 167(6):2875-81. doi:10.1016/j.ijcard.2012.07.021
132. Huang Z, Chen XJ, Qian C, Dong Q, Ding D, Wu QF, et al. Signal transducer and activator of transcription 3/microRNA-21 feedback loop contributes to atrial fibrillation by promoting atrial fibrosis in a rat sterile pericarditis model. Circ Arrhythm Electrophysiol (2016) 9(7):e003396. doi:10.1161/CIRCEP.115.003396
133. Wang J, Huang W, Xu R, Nie Y, Cao X, Meng J, et al. microRNA-24 reg-ulates cardiac fibrosis after myocardial infarction. J Cell Mol Med (2012) 16(9):2150-60. doi:10.1111/j.1582-4934.2012.01523.x
134. van Rooij E, Sutherland LB, Thatcher JE, DiMaio JM, Naseem RH, Marshall WS, et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci U S A (2008) 105(35):13027-32. doi:10.1073/pnas.0805038105
135. Zhou L, Wang L, Lu L, Jiang P, Sun H, Wang H. Inhibition of miR-29 by TGF-beta-Smad3 signaling through dual mechanisms promotes transdifferentia-tion of mouse myoblasts into myofibroblasts. PLoS One (2012) 7(3):e33766. doi:10.1371/journal.pone.0033766
136. Duisters RF, Tijsen AJ, Schroen B, Leenders JJ, Lentink V, van der Made I, et al. miR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling. Circ Res (2009) 104(2):170-8, 6p following 178. doi:10.1161/CIRCRESAHA.108.182535
137. Vegter EL, Schmitter D, Hagemeijer Y, Ovchinnikova ES, van der Harst P, Teerlink JR, et al. Use of biomarkers to establish potential role and function of circulating microRNAs in acute heart failure. Int J Cardiol (2016) 224:231-9. doi:10.1016/j.ijcard.2016.09.010
138. Ovchinnikova ES, Schmitter D, Vegter EL, Ter Maaten JM, Valente MA, Liu LC, et al. Signature of circulating microRNAs in patients with acute heart failure. Eur J Heart Fail (2016) 18(4):414-23. doi:10.1002/ejhf.332
139. Voellenkle C, van Rooij J, Cappuzzello C, Greco S, Arcelli D, Di Vito L, et al. microRNA signatures in peripheral blood mononuclear cells of chronic heart failure patients. Physiol Genomics (2010) 42(3):420-6. doi:10.1152/physiolgenomics.00211.2009
140. Qiang L, Hong L, Ningfu W, Huaihong C, Jing W. Expression of miR-126 and miR-508-5p in endothelial progenitor cells is associated with the prog-nosis of chronic heart failure patients. Int J Cardiol (2013) 168(3):2082-8. doi:10.1016/j.ijcard.2013.01.160
141. Tijsen AJ, Creemers EE, Moerland PD, de Windt LJ, van der Wal AC, Kok WE, et al. miR423-5p as a circulating biomarker for heart failure. Circ Res (2010) 106(6):1035-9. doi:10.1161/CIRCRESAHA.110.218297
142. Melman YF, Shah R, Danielson K, Xiao J, Simonson B, Barth A, et al. Circulating microRNA-30d is associated with response to cardiac resyn-chronization therapy in heart failure and regulates cardiomyocyte apoptosis: a translational pilot study. Circulation (2015) 131(25):2202-16. doi:10.1161/CIRCULATIONAHA.114.013220
143. Atluri P, Goldstone AB, Kobrin DM, Cohen JE, MacArthur JW, Howard JL, et al. Ventricular assist device implant in the elderly is associated with increased, but respectable risk: a multi-institutional study. Ann Thorac Surg (2013) 96(1):141-7. doi:10.1016/j.athoracsur.2013.04.010
144. Morley-Smith AC, Mills A, Jacobs S, Meyns B, Rega F, Simon AR, et al. Circulating microRNAs for predicting and monitoring response to mechan-ical circulatory support from a left ventricular assist device. Eur J Heart Fail (2014) 16(8):871-9. doi:10.1002/ejhf.116
145. Brook RD, Appel LJ, Rubenfire M, Ogedegbe G, Bisognano JD, Elliott WJ, et al. Beyond medications and diet: alternative approaches to lowering blood pressure: a scientific statement from the American Heart Association. Hypertension (2013) 61(6):1360-83. doi:10.1161/HYP.0b013e318293645f
146. Phillips RA. Current and future treatment of hypertension in the SPRINT era. Methodist Debakey Cardiovasc J (2015) 11(4):206-13. doi:10.14797/mdcj-11-4-206
147. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008. JAMA (2010) 303(20):2043-50. doi:10.1001/jama.2010.650
148. Chopra S, Baby C, Jacob JJ. Neuro-endocrine regulation of blood pres-sure. Indian J Endocrinol Metab (2011) 15(Suppl 4):S281-8. doi:10.4103/2230-8210.86860
149. Klimczak D, Jazdzewski K, Kuch M. Regulatory mechanisms in arterial hypertension: role of microRNA in pathophysiology and therapy. Blood Press (2017) 26(1):2-8. doi:10.3109/08037051.2016.1167355
150. Romaine SP, Charchar FJ, Samani NJ, Tomaszewski M. Circulating microR-NAs and hypertension -from new insights into blood pressure regulation to biomarkers of cardiovascular risk. Curr Opin Pharmacol (2016) 27:1-7. doi:10.1016/j.coph.2015.12.002
151. Mayet J, Hughes A. Cardiac and vascular pathophysiology in hypertension. Heart (2003) 89(9):1104-9. doi:10.1136/heart.89.9.1104
152. Jackson KL, Marques FZ, Watson AM, Palma-Rigo K, Nguyen-Huu TP, Morris BJ, et al. A novel interaction between sympathetic overactivity and aberrant regulation of renin by miR-181a in BPH/2J genetically hypertensive mice. Hypertension (2013) 62(4):775-81. doi:10.1161/HYPERTENSIONAHA.113.01701
153. Marques FZ, Campain AE, Tomaszewski M, Zukowska-Szczechowska E, Yang YH, Charchar FJ, et al. Gene expression profiling reveals renin mRNA overexpression in human hypertensive kidneys and a role for microRNAs. Hypertension (2011) 58(6):1093-8. doi:10.1161/HYPERTENSIONAHA.111.180729
154. Kohlstedt K, Trouvain C, Boettger T, Shi L, Fisslthaler B, Fleming I. AMP-activated protein kinase regulates endothelial cell angiotensin-converting enzyme expression via p53 and the post-transcriptional regu-lation of microRNA-143/145. Circ Res (2013) 112(8):1150-8. doi:10.1161/CIRCRESAHA.113.301282
155. Boettger T, Beetz N, Kostin S, Schneider J, Krüger M, Hein L, et al. Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster. J Clin Invest (2009) 119(9):2634-47. doi:10.1172/JCI38864
156. Feihl F, Liaudet L, Levy BI, Waeber B. Hypertension and microvascular remodelling. Cardiovasc Res (2008) 78(2):274-85. doi:10.1093/cvr/cvn022
157. Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev (2000) 52(1):11-34.
158. Kemp JR, Unal H, Desnoyer R, Yue H, Bhatnagar A, Karnik SS. Angiotensin II-regulated microRNA 483-3p directly targets multiple components of the renin-angiotensin system. J Mol Cell Cardiol (2014) 75:25-39. doi:10.1016/j.yjmcc.2014.06.008
159. Eskildsen TV, Jeppesen PL, Schneider M, Nossent AY, Sandberg MB, Hansen PB, et al. Angiotensin II regulates microRNA-132/-212 in hyper-tensive rats and humans. Int J Mol Sci (2013) 14(6):11190-207. doi:10.3390/ijms140611190
160. Zhan Y, Brown C, Maynard E, Anshelevich A, Ni W, Ho IC, et al. Ets-1 is a critical regulator of Ang II-mediated vascular inflammation and remodeling. J Clin Invest (2005) 115(9):2508-16. doi:10.1172/JCI24403
161. Yang Y, Zhou Y, Cao Z, Tong XZ, Xie HQ, Luo T, et al. miR-155 functions downstream of angiotensin II receptor subtype 1 and calcineurin to regulate cardiac hypertrophy. Exp Ther Med (2016) 12(3):1556-62. doi:10.3892/etm.2016.3506
162. Zhu N, Zhang D, Chen S, Liu X, Lin L, Huang X, et al. Endothelial enriched microRNAs regulate angiotensin II-induced endothelial inflammation and migration. Atherosclerosis (2011) 215(2):286-93. doi:10.1016/j.atherosclerosis.2010.12.024
163. Yang LX, Liu G, Zhu GF, Liu H, Guo RW, Qi F, et al. microRNA-155 inhibits angiotensin II-induced vascular smooth muscle cell proliferation. J Renin Angiotensin Aldosterone Syst (2014) 15(2):109-16. doi:10.1177/1470320313503693
164. Schulz R, Rassaf T, Massion PB, Kelm M, Balligand JL. Recent advances in the understanding of the role of nitric oxide in cardiovascular homeostasis. Pharmacol Ther (2005) 108(3):225-56. doi:10.1016/j.pharmthera.2005.04.005
165. Sun HX, Zeng DY, Li RT, Pang RP, Yang H, Hu YL, et al. Essential role of microRNA-155 in regulating endothelium-dependent vasorelaxation by tar-geting endothelial nitric oxide synthase. Hypertension (2012) 60(6):1407-14. doi:10.1161/HYPERTENSIONAHA.112.197301
166. Yang Z, Venardos K, Jones E, Morris BJ, Chin-Dusting J, Kaye DM. Identification of a novel polymorphism in the 3′UTR of the l-arginine transporter gene SLC7A1: contribution to hypertension and endo-thelial dysfunction. Circulation (2007) 115(10):1269-74. doi:10.1161/CIRCULATIONAHA.106.665836
167. Yang Z, Kaye DM. Mechanistic insights into the link between a polymor-phism of the 3′UTR of the SLC7A1 gene and hypertension. Hum Mutat (2009) 30(3):328-33. doi:10.1002/humu.20891
168. Li P, Yin YL, Guo T, Sun XY, Ma H, Zhu ML, et al. Inhibition of aberrant microRNA-133a expression in endothelial cells by statin prevents endothelial dysfunction by targeting GTP cyclohydrolase 1 in vivo. Circulation (2016) 134(22):1752-65. doi:10.1161/CIRCULATIONAHA.116.017949
169. Briones AM, Touyz RM. Oxidative stress and hypertension: current concepts. Curr Hypertens Rep (2010) 12(2):135-42. doi:10.1007/s11906-010-0100-z
170. Li H, Zhang X, Wang F, Zhou L, Yin Z, Fan J, et al. microRNA-21 lowers blood pressure in spontaneous hypertensive rats by upregulating mitochondrial translation. Circulation (2016) 134(10):734-51. doi:10.1161/CIRCULATIONAHA.116.023926
171. Nemecz M, Alexandru N, Tanko G, Georgescu A. Role of microRNA in endothelial dysfunction and hypertension. Curr Hypertens Rep (2016) 18(12):87. doi:10.1007/s11906-016-0696-8
172. Li S, Zhu J, Zhang W, Chen Y, Zhang K, Popescu LM, et al. Signature microRNA expression profile of essential hypertension and its novel link to human cytomegalovirus infection. Circulation (2011) 124(2):175-84. doi:10.1161/CIRCULATIONAHA.110.012237
173. Goto M, Mukoyama M, Sugawara A, Suganami T, Kasahara M, Yahata K, et al. Expression and role of angiotensin II type 2 receptor in the kidney and mesangial cells of spontaneously hypertensive rats. Hypertens Res (2002) 25(1):125-33. doi:10.1291/hypres.25.125
174. Bachmaier K, Neu N, Pummerer C, Duncan GS, Mak TW, Matsuyama T, et al. iNOS expression and nitrotyrosine formation in the myocardium in response to inflammation is controlled by the interferon regulatory transcrip-tion factor 1. Circulation (1997) 96(2):585-91.
175. Yang Q, Jia C, Wang P, Xiong M, Cui J, Li L, et al. microRNA-505 identified from patients with essential hypertension impairs endothelial cell migration and tube formation. Int J Cardiol (2014) 177(3):925-34. doi:10.1016/j.ijcard.2014.09.204
176. Karolina DS, Tavintharan S, Armugam A, Sepramaniam S, Pek SL, Wong MT, et al. Circulating miRNA profiles in patients with metabolic syndrome. J Clin Endocrinol Metab (2012) 97(12):E2271-6. doi:10.1210/jc.2012-1996
177. Kontaraki JE, Marketou ME, Zacharis EA, Parthenakis FI, Vardas PE. Differential expression of vascular smooth muscle-modulating microRNAs in human peripheral blood mononuclear cells: novel targets in essential hyper-tension. J Hum Hypertens (2014) 28(8):510-6. doi:10.1038/jhh.2013.117
178. Kontaraki JE, Marketou ME, Zacharis EA, Parthenakis FI, Vardas PE. microRNA-9 and microRNA-126 expression levels in patients with essential hypertension: potential markers of target-organ damage. J Am Soc Hypertens (2014) 8(6):368-75. doi:10.1016/j.jash.2014.03.324
179. Mandraffino G, Imbalzano E, Sardo MA, D’Ascola A, Mamone F, Lo Gullo A, et al. Circulating progenitor cells in hypertensive patients with different degrees of cardiovascular involvement. J Hum Hypertens (2014) 28(9):543-50. doi:10.1038/jhh.2014.7
180. Finney AC, Stokes KY, Pattillo CB, Orr AW. Integrin signaling in atherosclero-sis. Cell Mol Life Sci (2017) 74(12):2263-82. doi:10.1007/s00018-017-2490-4
181. Feinberg MW, Moore KJ. microRNA regulation of atherosclerosis. Circ Res (2016) 118(4):703-20. doi:10.1161/CIRCRESAHA.115.306300
182. Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab (2006) 3(2):87-98. doi:10.1016/j.cmet.2006.01.005
183. Elmén J, Lindow M, Silahtaroglu A, Bak M, Christensen M, Lind-Thomsen A, et al. Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver. Nucleic Acids Res (2008) 36(4):1153-62. doi:10.1093/nar/gkm1113
184. Elmén J, Lindow M, Schütz S, Lawrence M, Petri A, Obad S, et al. LNA-mediated microRNA silencing in non-human primates. Nature (2008) 452(7189):896-9. doi:10.1038/nature06783
185. Soh J, Iqbal J, Queiroz J, Fernandez-Hernando C, Hussain MM. microRNA-30c reduces hyperlipidemia and atherosclerosis in mice by decreasing lipid synthesis and lipoprotein secretion. Nat Med (2013) 19(7):892-900. doi:10.1038/nm.3200
186. Tall AR, Yvan-Charvet L, Terasaka N, Pagler T, Wang N. HDL, ABC trans-porters, and cholesterol efflux: implications for the treatment of atherosclero-sis. Cell Metab (2008) 7(5):365-75. doi:10.1016/j.cmet.2008.03.001
187. Wagschal A, Najafi-Shoushtari SH, Wang L, Goedeke L, Sinha S, deLemos AS, et al. Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. Nat Med (2015) 21(11):1290-7. doi:10.1038/nm.3980
188. Rayner KJ, Sheedy FJ, Esau CC, Hussain FN, Temel RE, Parathath S, et al. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J Clin Invest (2011) 121(7):2921-31. doi:10.1172/JCI57275
189. Rayner KJ, Esau CC, Hussain FN, McDaniel AL, Marshall SM, van Gils JM, et al. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature (2011) 478(7369):404-7. doi:10.1038/nature10486
190. Kumar S, Kim CW, Simmons RD, Jo H. Role of flow-sensitive microRNAs in endothelial dysfunction and atherosclerosis: mechanosensitive athero-miRs. Arterioscler Thromb Vasc Biol (2014) 34(10):2206-16. doi:10.1161/ATVBAHA.114.303425
191. Fang Y, Shi C, Manduchi E, Civelek M, Davies PF. microRNA-10a regulation of proinflammatory phenotype in athero-susceptible endothelium in vivo and in vitro. Proc Natl Acad Sci U S A (2010) 107(30):13450-5. doi:10.1073/pnas.1002120107
192. Hergenreider E, Heydt S, Tréguer K, Boettger T, Horrevoets AJ, Zeiher AM, et al. Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat Cell Biol (2012) 14(3):249-56. doi:10.1038/ncb2441
193. Wu W, Xiao H, Laguna-Fernandez A, Villarreal G, Wang KC, Geary GG, et al. Flow-dependent regulation of Kruppel-like factor 2 is mediated by microRNA-92a. Circulation (2011) 124(5):633-41. doi:10.1161/CIRCULATIONAHA.110.005108
194. Daniel JM, Penzkofer D, Teske R, Dutzmann J, Koch A, Bielenberg W, et al. Inhibition of miR-92a improves re-endothelialization and prevents neointima formation following vascular injury. Cardiovasc Res (2014) 103(4):564-72. doi:10.1093/cvr/cvu162
195. Sun X, Icli B, Wara AK, Belkin N, He S, Kobzik L, et al. microRNA-181b regulates NF-κB-mediated vascular inflammation. J Clin Invest (2012) 122(6):1973-90. doi:10.1172/JCI61495
196. Sun X, He S, Wara AK, Icli B, Shvartz E, Tesmenitsky Y, et al. Systemic delivery of microRNA-181b inhibits nuclear factor-κB activation, vascular inflammation, and atherosclerosis in apolipoprotein E-deficient mice. Circ Res (2014) 114(1):32-40. doi:10.1161/CIRCRESAHA.113.302089
197. Hulsmans M, Sinnaeve P, Van der Schueren B, Mathieu C, Janssens S, Holvoet P. Decreased miR-181a expression in monocytes of obese patients is associated with the occurrence of metabolic syndrome and coronary artery disease. J Clin Endocrinol Metab (2012) 97(7):E1213-8. doi:10.1210/jc.2012-1008
198. Ma S, Tian XY, Zhang Y, Mu C, Shen H, Bismuth J, et al. E-selectin-targeting delivery of microRNAs by microparticles ameliorates endothelial inflammation and atherosclerosis. Sci Rep (2016) 6:22910. doi:10.1038/srep22910
199. Zhang M, Wu JF, Chen WJ, Tang SL, Mo ZC, Tang YY, et al. microRNA-27a/b regulates cellular cholesterol efflux, influx and esterification/hydrolysis in THP-1 macrophages. Atherosclerosis (2014) 234(1):54-64. doi:10.1016/j.atherosclerosis.2014.02.008
200. Meiler S, Baumer Y, Toulmin E, Seng K, Boisvert WA. microRNA 302a is a novel modulator of cholesterol homeostasis and atherosclerosis. Arterioscler Thromb Vasc Biol (2015) 35(2):323-31. doi:10.1161/ATVBAHA.114.304878
201. Sun D, Zhang J, Xie J, Wei W, Chen M, Zhao X. miR-26 controls LXR-dependent cholesterol efflux by targeting ABCA1 and ARL7. FEBS Lett (2012) 586(10):1472-9. doi:10.1016/j.febslet.2012.03.068
202. Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol (2013) 13(10):709-21. doi:10.1038/nri3520
203. Ouimet M, Ediriweera HN, Gundra UM, Sheedy FJ, Ramkhelawon B, Hutchison SB, et al. microRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. J Clin Invest (2015) 125(12):4334-48. doi:10.1172/JCI81676
204. Gabunia K, Herman AB, Ray M, Kelemen SE, England RN, Cadena RD, et al. Induction of miR133a expression by IL-19 targets LDLRAP1 and reduces oxLDL uptake in VSMC. J Mol Cell Cardiol (2017) 105:38-48. doi:10.1016/j.yjmcc.2017.02.005
205. Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta N, et al. microRNA-145 targeted therapy reduces atherosclerosis. Circulation (2012) 126(11 Suppl 1): S81-90. doi:10.1161/CIRCULATIONAHA.111.084186
206. Cocco G, Jerie P. New concepts in the therapy of atrial fibrillation. Cardiol J (2016) 23(1):3-11. doi:10.5603/CJ.a2015.0053
207. Karamichalakis N, Letsas KP, Vlachos K, Georgopoulos S, Bakalakos A, Efremidis M, et al. Managing atrial fibrillation in the very elderly patient: challenges and solutions. Vasc Health Risk Manag (2015) 11:555-62. doi:10.2147/VHRM.S83664
208. Sharma M, Cornelius VR, Patel JP, Davies JG, Molokhia M. Efficacy and harms of direct oral anticoagulants in the elderly for stroke prevention in atrial fibrillation and secondary prevention of venous thromboembolism: systematic review and meta-analysis. Circulation (2015) 132(3):194-204. doi:10.1161/CIRCULATIONAHA.114.013267
209. Zhang Y, Dong D, Yang B. Atrial remodeling in atrial fibrillation and asso-ciation between microRNA network and atrial fibrillation. Sci China Life Sci (2011) 54(12):1097-102. doi:10.1007/s11427-011-4241-3
210. Luo X, Yang B, Nattel S. microRNAs and atrial fibrillation: mechanisms and translational potential. Nat Rev Cardiol (2015) 12(2):80-90. doi:10.1038/nrcardio.2014.178
211. Sharma D, Li G, Xu G, Liu Y, Xu Y. Atrial remodeling in atrial fibrillation and some related microRNAs. Cardiology (2011) 120(2):111-21. doi:10.1159/000334434
212. Yang B, Lin H, Xiao J, Lu Y, Luo X, Li B, et al. The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med (2007) 13(4):486-91. doi:10.1038/nm1569
213. Jia X, Zheng S, Xie X, Zhang Y, Wang W, Wang Z, et al. microRNA-1 accelerates the shortening of atrial effective refractory period by regulating KCNE1 and KCNB2 expression: an atrial tachypacing rabbit model. PLoS One (2013) 8(12):e85639. doi:10.1371/journal.pone.0085639
214. Lu Y, Hou S, Huang D, Luo X, Zhang J, Chen J, et al. Expression profile analysis of circulating microRNAs and their effects on ion channels in Chinese atrial fibrillation patients. Int J Clin Exp Med (2015) 8(1):845-53.
215. Terentyev D, Belevych AE, Terentyeva R, Martin MM, Malana GE, Kuhn DE, et al. miR-1 overexpression enhances Ca(2+) release and promotes cardiac arrhythmogenesis by targeting PP2A regulatory subunit B56alpha and causing CaMKII-dependent hyperphosphorylation of RyR2. Circ Res (2009) 104(4):514-21. doi:10.1161/CIRCRESAHA.108.181651
216. Tao H, Shi KH, Yang JJ, Li J. Epigenetic mechanisms in atrial fibrillation: new insights and future directions. Trends Cardiovasc Med (2016) 26(4):306-18. doi:10.1016/j.tcm.2015.08.006
217. Lu Y, Zhang Y, Wang N, Pan Z, Gao X, Zhang F, et al. microRNA-328 contrib-utes to adverse electrical remodeling in atrial fibrillation. Circulation (2010) 122(23):2378-87. doi:10.1161/CIRCULATIONAHA.110.958967
218. Ling TY, Wang XL, Chai Q, Lau TW, Koestler CM, Park SJ, et al. Regulation of the SK3 channel by microRNA-499 -potential role in atrial fibrillation. Heart Rhythm (2013) 10(7):1001-9. doi:10.1016/j.hrthm.2013.03.005
219. Luo X, Pan Z, Shan H, Xiao J, Sun X, Wang N, et al. microRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation. J Clin Invest (2013) 123(5):1939-51. doi:10.1172/JCI62185
220. Liu T, Zhong S, Rao F, Xue Y, Qi Z, Wu S. Catheter ablation restores decreased plasma miR-409-3p and miR-432 in atrial fibrillation patients. Europace (2016) 18(1):92-9. doi:10.1093/europace/euu366
221. McManus DD, Tanriverdi K, Lin H, Esa N, Kinno M, Mandapati D, et al. Plasma microRNAs are associated with atrial fibrillation and change after catheter ablation (the miRhythm study). Heart Rhythm (2015) 12(1):3-10. doi:10.1016/j.hrthm.2014.09.050
222. Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global esti-mates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract (2011) 94(3):311-21. doi:10.1016/j.diabres.2011.10.029
223. Sloan FA, Bethel MA, Ruiz D, Shea AM, Shea AH, Feinglos MN. The growing burden of diabetes mellitus in the US elderly population. Arch Intern Med (2008) 168(2):192-9; discussion 199. doi:10.1001/archinternmed.2007.35
224. Lin Y, Sun Z. Current views on type 2 diabetes. J Endocrinol (2010) 204(1):1-11. doi:10.1677/JOE-09-0260
225. Guay C, Regazzi R. Circulating microRNAs as novel biomarkers for diabetes mellitus. Nat Rev Endocrinol (2013) 9(9):513-21. doi:10.1038/nrendo.2013.86
226. Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE, et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature (2004) 432(7014):226-30. doi:10.1038/nature03076
227. El Ouaamari A, Baroukh N, Martens GA, Lebrun P, Pipeleers D, van Obberghen E. miR-375 targets 3′-phosphoinositide-dependent protein kinase-1 and regulates glucose-induced biological responses in pancreatic beta-cells. Diabetes (2008) 57(10):2708-17. doi:10.2337/db07-1614
228. Poy MN, Hausser J, Trajkovski M, Braun M, Collins S, Rorsman P, et al. miR-375 maintains normal pancreatic alpha-and beta-cell mass. Proc Natl Acad Sci U S A (2009) 106(14):5813-8. doi:10.1073/pnas.0810550106
229. Li X. miR-375, a microRNA related to diabetes. Gene (2014) 533(1):1-4. doi:10.1016/j.gene.2013.09.105
230. Hashimoto N, Tanaka T. Role of miRNAs in the pathogenesis and suscep-tibility of diabetes mellitus. J Hum Genet (2017) 62(2):141-50. doi:10.1038/jhg.2016.150
231. Sebastiani G, Po A, Miele E, Ventriglia G, Ceccarelli E, Bugliani M, et al. microRNA-124a is hyperexpressed in type 2 diabetic human pancreatic islets and negatively regulates insulin secretion. Acta Diabetol (2015) 52(3):523-30. doi:10.1007/s00592-014-0675-y
232. Pullen TJ, da Silva Xavier G, Kelsey G, Rutter GA. miR-29a and miR-29b contribute to pancreatic beta-cell-specific silencing of monocarboxylate transporter 1 (Mct1). Mol Cell Biol (2011) 31(15):3182-94. doi:10.1128/MCB.01433-10
233. Yang WM, Jeong HJ, Park SY, Lee W. Induction of miR-29a by saturated fatty acids impairs insulin signaling and glucose uptake through transla-tional repression of IRS-1 in myocytes. FEBS Lett (2014) 588(13):2170-6. doi:10.1016/j.febslet.2014.05.011
234. Trajkovski M, Hausser J, Soutschek J, Bhat B, Akin A, Zavolan M, et al. microRNAs 103 and 107 regulate insulin sensitivity. Nature (2011) 474(7353):649-53. doi:10.1038/nature10112
235. Feng J, Xing W, Xie L. Regulatory roles of microRNAs in diabetes. Int J Mol Sci (2016) 17(10): 1729. doi:10.3390/ijms17101729
236. Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, et al. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res (2010) 107(6):810-7. doi:10.1161/CIRCRESAHA.110.226357
237. Kong L, Zhu J, Han W, Jiang X, Xu M, Zhao Y, et al. Significance of serum microRNAs in pre-diabetes and newly diagnosed type 2 diabetes: a clinical study. Acta Diabetol (2011) 48(1):61-9. doi:10.1007/s00592-010-0226-0
238. Zhang T, Lv C, Li L, Chen S, Liu S, Wang C, et al. Plasma miR-126 is a poten-tial biomarker for early prediction of type 2 diabetes mellitus in susceptible individuals. Biomed Res Int (2013) 2013:761617. doi:10.1155/2013/761617
239. Yan S, Wang T, Huang S, Di Y, Huang Y, Liu X, et al. Differential expression of microRNAs in plasma of patients with prediabetes and newly diagnosed type 2 diabetes. Acta Diabetol (2016) 53(5):693-702. doi:10.1007/s00592-016-0837-1
240. Chien HY, Chen CY, Chiu YH, Lin YC, Li WC. Differential microRNA profiles predict diabetic nephropathy progression in Taiwan. Int J Med Sci (2016) 13(6):457-65. doi:10.7150/ijms.15548
241. Al-Kafaji G, Al-Mahroos G, Abdulla Al-Muhtaresh H, Sabry MA, Abdul Razzak R, Salem AH. Circulating endothelium-enriched microRNA-126 as a potential biomarker for coronary artery disease in type 2 diabetes mellitus patients. Biomarkers (2016) 22(3-4):268-78. doi:10.1080/1354750X.2016.1204004
242. Nielsen LB, Wang C, Sorensen K, Bang-Berthelsen CH, Hansen L, Andersen ML, et al. Circulating levels of microRNA from children with newly diagnosed type 1 diabetes and healthy controls: evidence that miR-25 associates to residual beta-cell function and glycaemic control during disease progression. Exp Diabetes Res (2012) 2012:896362. doi:10.1155/2012/896362
243. Osipova J, Fischer DC, Dangwal S, Volkmann I, Widera C, Schwarz K, et al. Diabetes-associated microRNAs in pediatric patients with type 1 diabetes mellitus: a cross-sectional cohort study. J Clin Endocrinol Metab (2014) 99(9):E1661-5. doi:10.1210/jc.2013-3868
244. Salas-Perez F, Codner E, Valencia E, Pizarro C, Carrasco E, Perez-Bravo F. microRNAs miR-21a and miR-93 are down regulated in peripheral blood mononuclear cells (PBMCs) from patients with type 1 diabetes. Immunobiology (2013) 218(5):733-7. doi:10.1016/j.imbio.2012.08.276
245. Chow SL, Maisel AS, Anand I, Bozkurt B, de Boer RA, Felker GM, et al. Role of biomarkers for the prevention, assessment, and management of heart failure: a scientific statement from the American Heart Association. Circulation (2017) 135:e1054-e1091. doi:10.1161/CIR.0000000000000490
246. Bouras G, Deftereos S. Editorial (hot topic: cardiovascular disease biomarkers: from tradition to modernity). Curr Top Med Chem (2013) 13(2):79-81. doi:10.2174/1568026611313020001
247. Giles T. Biomarkers, cardiovascular disease, and hypertension. J Clin Hypertens (Greenwich) (2013) 15(1):1. doi:10.1111/jch.12014
248. Sebastiani P, Thyagarajan B, Sun F, Schupf N, Newman AB, Montano M, et al. Biomarker signatures of aging. Aging Cell (2017) 16(2):329-38. doi:10.1111/acel.12557
249. Wagner KH, Cameron-Smith D, Wessner B, Franzke B. Biomarkers of aging: from function to molecular biology. Nutrients (2016) 8(6):E338. doi:10.3390/nu8060338
250. Navickas R, Gal D, Laucevičius A, Taparauskaitė A, Zdanytė M, Holvoet P. Identifying circulating microRNAs as biomarkers of cardiovascular disease: a systematic review. Cardiovasc Res (2016) 111(4):322-37. doi:10.1093/cvr/cvw174
251. Cavarretta E, Frati G. microRNAs in coronary heart disease: ready to enter the clinical arena? Biomed Res Int (2016) 2016:2150763. doi:10.1155/2016/2150763
252. Blondal T, Jensby Nielsen S, Baker A, Andreasen D, Mouritzen P, Wrang Teilum M, et al. Assessing sample and miRNA profile quality in serum and plasma or other biofluids. Methods (2013) 59(1):S1-6. doi:10.1016/j.ymeth.2012.09.015
253. Correia CN, Nalpas NC, McLoughlin KE, Browne JA, Gordon SV, MacHugh DE, et al. Circulating microRNAs as potential biomarkers of infectious disease. Front Immunol (2017) 8:118. doi:10.3389/fimmu.2017.00118
254. McDonald JS, Milosevic D, Reddi HV, Grebe SK, Algeciras-Schimnich A. Analysis of circulating microRNA: preanalytical and analytical challenges. Clin Chem (2011) 57(6):833-40. doi:10.1373/clinchem.2010.157198
255. Meyer SU, Pfaffl MW, Ulbrich SE. Normalization strategies for microRNA profiling experiments: a ‘normal’ way to a hidden layer of complexity? Biotechnol Lett (2010) 32(12):1777-88. doi:10.1007/s10529-010-0380-z
256. Kok MG, Halliani A, Moerland PD, Meijers JC, Creemers EE, Pinto-Sietsma SJ. Normalization panels for the reliable quantification of circulating microRNAs by RT-qPCR. FASEB J (2015) 29(9):3853-62. doi:10.1096/fj.15-271312
257. Marabita F, de Candia P, Torri A, Tegnér J, Abrignani S, Rossi RL. Normalization of circulating microRNA expression data obtained by quantitative real-time RT-PCR. Brief Bioinform (2016) 17(2):204-12. doi:10.1093/bib/bbv056
258. Vigneron N, Meryet-Figuière M, Guttin A, Issartel JP, Lambert B, Briand M, et al. Towards a new standardized method for circulating miRNAs profiling in clinical studies: interest of the exogenous normalization to improve miRNA signature accuracy. Mol Oncol (2016) 10(7):981-92. doi:10.1016/j.molonc.2016.03.005
259. Pritchard CC, Cheng HH, Tewari M. microRNA profiling: approaches and considerations. Nat Rev Genet (2012) 13(5):358-69. doi:10.1038/nrg3198
260. Laitala-Leinonen T. Update on the development of microRNA and siRNA molecules as regulators of cell physiology. Recent Pat DNA Gene Seq (2010) 4(2):113-21. doi:10.2174/187221510793205755
261. Recent patent applications in microRNAs. Nat Biotechnol (2006) 24(1):44. doi:10.1038/nbt0106-44
262. Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med (2013) 368(18):1685-94. doi:10.1056/NEJMoa1209026
263. Hackl M, Brunner S, Fortschegger K, Schreiner C, Micutkova L, Mück C, et al. miR-17, miR-19b, miR-20a, and miR-106a are down-regulated in human aging. Aging Cell (2010) 9(2):291-6. doi:10.1111/j.1474-9726.2010.00549.x