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• W2073306670 abstract "HomeCirculation ResearchVol. 115, No. 10Battle of the Bulge Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBBattle of the BulgemiR-195 Versus miR-29b in Aortic Aneurysm Joshua M. Spin and Philip S. Tsao Joshua M. SpinJoshua M. Spin From the Division of Cardiovascular Medicine, Stanford University School of Medicine, CA. Search for more papers by this author and Philip S. TsaoPhilip S. Tsao From the Division of Cardiovascular Medicine, Stanford University School of Medicine, CA. Search for more papers by this author Originally published24 Oct 2014https://doi.org/10.1161/CIRCRESAHA.114.305233Circulation Research. 2014;115:812–813Abdominal aortic aneurysm (AAA) is a potentially lethal condition, capable of progressing to acute rupture—a catastrophic event with an 80% mortality risk. A conservative estimate places annual deaths because of AAA in the United States at ≈15 000, although the actual burden is likely higher.1 These dilations are typically found within the infrarenal aortic segment but are only rarely symptomatic, causing them to remain undiscovered until they are either identified through coincident imaging or rupture occurs. Among the risk factors for AAA are male sex, advanced age, genetic predilection, and a history of tobacco use. No pharmacological approach in humans to date has successfully decreased AAA expansion or prevented rupture.2 Although surgery and endovascular stent grafting are highly effective in preventing death from larger AAAs, they are complex procedures with multiple potential complications. How then, might the battle against AAA be better waged?Article, see p 857MicroRNAs are intricately woven into a web of epigenetic pathophysiologic regulation. Modulation of any given micro RNA can alter the expression of dozens of target genes, including entire functional gene networks, thereby affecting the progression of a wide array of disease phenotypes. In recent reviews examining the role of microRNAs in AAA, we noted their remarkable potential, both to improve risk stratification and diagnosis and to alter vascular disease therapeutically. In this vein, exciting findings have been published for several microRNAs including miR-21, miR-26a, the miR-17-92-cluster, miRs-221/222, miR-133, miR-126, miR-143/145, miR-146a, miR-155, and miR-29b.3,4Of these candidates, the last (miR-29b) seems particularly promising. Remodeling of the extracellular matrix within the aortic adventitia and media is crucial for AAA progression, characterized by elastin fragmentation and loss and increased collagen turnover. miR-29b targets include numerous collagen genes and elastin. Furthermore, miR-29b modulation in vitro and in vivo can alter matrix metalloprotease (MMP) activity. miR-29b is differentially regulated in animal models of aneurysm and in human AAA tissue, and inhibition of miR-29b in murine models of AAA and Marfan syndrome has led to diminished aneurysm progression (while overexpression increases aneurysm growth and rupture rate).5–7In this issue of Circulation Research, Zampetaki et al examined miR-195, a member of the miR-15 family known to share many of the same targets as miR-29b.8,9 They found that miR-195 (alone of the miR-15 family) was increased in aneurysmal aortic tissue from angiotensin II–treated apolipoprotein E–deficient mice. Angiotensin II has previously been shown to induce or inhibit miR-15a, -15b, -16-1, and -16-2 in either rat or human smooth muscle cells, but not miR-195.10,11 Furthermore, although significant downregulation of miR-15a, miR-195, and miR-497 has been observed in tissue from dissected human thoracic aorta compared with normal aorta, Pahl et al’s expression profiling of human AAA tissue did not identify any differentially regulated miR-15 family members.12,13In human aortic smooth muscle cells, miR-195 mimic was able to suppress elastin expression, but unlike miR-29b, caused a nonsignificant increase in MMP9 activity and an increase in MMP2 expression. The authors then performed proteomic studies of human smooth muscle cells, confirming that miR-195 regulates numerous extracellular matrix elements, although not to the same extent as miR-29b (especially in terms of collagen repression).More disappointing were attempts at in vivo inhibition of miR-195 in the mouse AAA model. Although clear suppression of miR-195 in the aorta was achieved, correlating with increases in expression of elastin and collagens, there was no significant impact on aneurysm progression or subject survival (no in vivo miR-195-mimic experiments were performed). Immunohistochemistry showed increased Mmp9 expression in anti-miR-195–transfected aortae. In contrast, and confirming published data using the same model, anti-miR-29b led to improved survival and slowed aortic growth. Maegdefessel et al7 also demonstrated that systemic anti-miR-29b lowered MMP2 and MMP9 activity and expression in vivo.Zampetaki et al9 noted that antagomiR-29b had minimal effects on miR-29b levels in an aortic isograft model. This supports the conclusion in Maegdefessel et al7 that locked nucleic acid (LNA)-anti-miR-29b is not readily taken up by uninjured vessel wall. However, in both studies, uptake within the affected suprarenal aorta (angiotensin II murine model) was sufficient to alter disease progression and target expression. In contrast, anti-miR-195 diffused more readily into uninjured vasculature but did not abrogate disease. This is unusual, as in our experience intact endothelium often resists LNA-miR uptake. The authors attribute the contrasting in vivo results between anti-miR-195 and anti-miR-29b to their inverse regulatory effects on MMP activity. Given the known association between MMP activity and AAA severity and progression, this may well be the case.14Interestingly, in addition to its role in extracellular matrix regulation, miR-195 is a known tumor suppressor, which has been shown to inhibit growth and proliferation, promote apoptosis, and inhibit cellular migration in various tissues and cell types.15 In contrast another microRNA—miR-21—inhibits tumor suppressors, eliciting the opposite cellular responses from those attributed to miR-195, and pre-miR-21 administration has significantly curtailed murine AAA growth.16 It might have been expected that anti-miR-195 would, therefore, have similar effects. However, miR-195 is also known to suppress angiogenesis.17 Angiogenesis inhibition is believed to limit AAA progression, which might, therefore, have further undermined the effectiveness of anti-miR-195.18Zampetaki et al9 also suggest an intriguing role for miR-195 as an AAA biomarker, which miR-29b is unlikely to match (as it was barely detectable in human plasma samples). Circulating microRNAs are stable in human blood and detectable and measurable with high sensitivity and specificity, suggesting that they might make effective AAA biomarkers.19,20 Clinical studies have demonstrated changes in microRNA levels in association with cardiovascular disease phenotypes, although these have often been underpowered or lacking in matched controls.21,22 The authors examined 16 microRNAs in plasma from 73 participants from an aneurysm screening program, finding that miR-195 was inversely correlated with aneurysm size and disease classification. Although 4 other miRs also showed such association, they were closely correlated with miR-195, and after proper adjustment their association with aortic size diminished. Intriguingly, miR-133a and miR-145 emerged as significant after adjustment for miR-195, suggesting that further studies involving a combination approach might yield a robust biomarker panel. As in the work cited above, the sample size queried was small for a biomarker study, and these findings will require extensive verification and replication in larger data sets to prove clinical utility.Despite the similar target profiles of miR-29b and miR-195, it remains to be seen whether the first may someday triumph on the field of therapeutic AAA abrogation and whether the latter will fulfill its promise as a predictive biomarker of AAA progression.Sources of FundingThis work is supported by research grants from the National Institutes of Health (1P50HL083800-01; 1HL-105299 and 1HL122939 to P.S. Tsao).DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Philip S. Tsao, PhD, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5406. E-mail [email protected]References1. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Executive summary: heart disease and stroke statistics–2013 update: a report from the American Heart Association.Circulation. 2013; 127:143–152.LinkGoogle Scholar2. Lu H, Rateri DL, Bruemmer D, Cassis LA, Daugherty A. Novel mechanisms of abdominal aortic aneurysms.Curr Atheroscler Rep. 2012; 14:402–412.CrossrefMedlineGoogle Scholar3. Adam M, Raaz U, Spin JM, Tsao PS. MicroRNAs in abdominal aortic aneurysm [published online ahead of print May 13, 2014].Curr Vasc Pharmacol. Google Scholar4. Maegdefessel L, Spin JM, Adam M, Raaz U, Toh R, Nakagami F, Tsao PS. Micromanaging abdominal aortic aneurysms.Int J Mol Sci. 2013; 14:14374–14394.CrossrefMedlineGoogle Scholar5. Boon RA, Seeger T, Heydt S, Fischer A, Hergenreider E, Horrevoets AJ, Vinciguerra M, Rosenthal N, Sciacca S, Pilato M, van Heijningen P, Essers J, Brandes RP, Zeiher AM, Dimmeler S. MicroRNA-29 in aortic dilation: implications for aneurysm formation.Circ Res. 2011; 109:1115–1119.LinkGoogle Scholar6. Merk DR, Chin JT, Dake BA, Maegdefessel L, Miller MO, Kimura N, Tsao PS, Iosef C, Berry GJ, Mohr FW, Spin JM, Alvira CM, Robbins RC, Fischbein MP. miR-29b participates in early aneurysm development in Marfan syndrome.Circ Res. 2012; 110:312–324.LinkGoogle Scholar7. Maegdefessel L, Azuma J, Toh R, Merk DR, Deng A, Chin JT, Raaz U, Schoelmerich AM, Raiesdana A, Leeper NJ, McConnell MV, Dalman RL, Spin JM, Tsao PS. Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development.J Clin Invest. 2012; 122:497–506.CrossrefMedlineGoogle Scholar8. Ott CE, Grünhagen J, Jäger M, Horbelt D, Schwill S, Kallenbach K, Guo G, Manke T, Knaus P, Mundlos S, Robinson PN. MicroRNAs differentially expressed in postnatal aortic development downregulate elastin via 3’ UTR and coding-sequence binding sites.PLoS One. 2011; 6:e16250.CrossrefMedlineGoogle Scholar9. Zampetaki A, Attia R, Mayr U, et al. Role of miR-195 in aortic aneurysmal disease.Circ Res. 2014; 115:857–866.LinkGoogle Scholar10. Jin W, Reddy MA, Chen Z, Putta S, Lanting L, Kato M, Park JT, Chandra M, Wang C, Tangirala RK, Natarajan R. Small RNA sequencing reveals microRNAs that modulate angiotensin II effects in vascular smooth muscle cells.J Biol Chem. 2012; 287:15672–15683.CrossrefMedlineGoogle Scholar11. 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.CrossrefMedlineGoogle Scholar12. Liao M, Zou S, Weng J, Hou L, Yang L, Zhao Z, Bao J, Jing Z. A microRNA profile comparison between thoracic aortic dissection and normal thoracic aorta indicates the potential role of microRNAs in contributing to thoracic aortic dissection pathogenesis.J Vasc Surg. 2011; 53:1341–1349 e1343.CrossrefMedlineGoogle Scholar13. Pahl MC, Derr K, Gäbel G, Hinterseher I, Elmore JR, Schworer CM, Peeler TC, Franklin DP, Gray JL, Carey DJ, Tromp G, Kuivaniemi H. MicroRNA expression signature in human abdominal aortic aneurysms.BMC Med Genomics. 2012; 5:25.CrossrefMedlineGoogle Scholar14. Deng GG, Martin-McNulty B, Sukovich DA, Freay A, Halks-Miller M, Thinnes T, Loskutoff DJ, Carmeliet P, Dole WP, Wang YX. Urokinase-type plasminogen activator plays a critical role in angiotensin II-induced abdominal aortic aneurysm.Circ Res. 2003; 92:510–517.LinkGoogle Scholar15. He JF, Luo YM, Wan XH, Jiang D. Biogenesis of MiRNA-195 and its role in biogenesis, the cell cycle, and apoptosis.J Biochem Mol Toxicol. 2011; 25:404–408.CrossrefMedlineGoogle Scholar16. Maegdefessel L, Azuma J, Toh R, Deng A, Merk DR, Raiesdana A, Leeper NJ, Raaz U, Schoelmerich AM, McConnell MV, Dalman RL, Spin JM, Tsao PS. MicroRNA-21 Blocks Abdominal Aortic Aneurysm Development and Nicotine-Augmented Expansion.Sci Transl Med. 2012; 4:122ra122.CrossrefGoogle Scholar17. Wang R, Zhao N, Li S, Fang JH, Chen MX, Yang J, Jia WH, Yuan Y, Zhuang SM. MicroRNA-195 suppresses angiogenesis and metastasis of hepatocellular carcinoma by inhibiting the expression of VEGF, VAV2, and CDC42.Hepatology. 2013; 58:642–653.CrossrefMedlineGoogle Scholar18. Tedesco MM, Terashima M, Blankenberg FG, Levashova Z, Spin JM, Backer MV, Backer JM, Sho M, Sho E, McConnell MV, Dalman RL. Analysis of in situ and ex vivo vascular endothelial growth factor receptor expression during experimental aortic aneurysm progression.Arterioscler Thromb Vasc Biol. 2009; 29:1452–1457.LinkGoogle Scholar19. Engelhardt S. Small RNA biomarkers come of age.J Am Coll Cardiol. 2012; 60:300–303.CrossrefMedlineGoogle Scholar20. Reid G, Kirschner MB, van Zandwijk N. Circulating microRNAs: association with disease and potential use as biomarkers.Crit Rev Oncol Hematol. 2011; 80:193–208.CrossrefMedlineGoogle Scholar21. Mendell JT, Olson EN. MicroRNAs in stress signaling and human disease.Cell. 2012; 148:1172–1187.CrossrefMedlineGoogle Scholar22. Zampetaki A, Willeit P, Tilling L, Drozdov I, Prokopi M, Renard JM, Mayr A, Weger S, Schett G, Shah A, Boulanger CM, Willeit J, Chowienczyk PJ, Kiechl S, Mayr M. Prospective study on circulating MicroRNAs and risk of myocardial infarction.J Am Coll Cardiol. 2012; 60:290–299.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Zhou Y, Wang J, Xue Y, Fang A, Wu S, Huang K, Tao L, Wang J, Shen Y, Wang J, Pan L, Li L and Ji K (2017) Microarray Analysis Reveals a Potential Role of lncRNA Expression in 3,4-Benzopyrene/Angiotensin II-Activated Macrophage in Abdominal Aortic Aneurysm, Stem Cells International, 10.1155/2017/9495739, 2017, (1-11), . Sandrim V, Eleuterio N, Pilan E, Tanus-Santos J, Fernandes K and Cavalli R (2016) Plasma levels of increased miR-195-5p correlates with the sFLT-1 levels in preeclampsia, Hypertension in Pregnancy, 10.3109/10641955.2015.1122034, 35:2, (150-158), Online publication date: 2-Apr-2016. Zhang W, Shang T, Huang C, Yu T, Liu C, Qiao T, Huang D, Liu Z and Liu C (2015) Plasma microRNAs serve as potential biomarkers for abdominal aortic aneurysm, Clinical Biochemistry, 10.1016/j.clinbiochem.2015.04.016, 48:15, (988-992), Online publication date: 1-Oct-2015. Ma X, Yao H, Yang Y, Jin L, Wang Y, Wu L, Yang S and Cheng K (2018) miR-195 suppresses abdominal aortic aneurysm through the TNF-α/NF-κB and VEGF/PI3K/Akt pathway, International Journal of Molecular Medicine, 10.3892/ijmm.2018.3426 Goliopoulou A, Oikonomou E, Antonopoulos A, Koumallos N, Gazouli M, Theofilis P, Mystakidi V, Pantelidis P, Vavuranakis M, Siasos G and Tousoulis D (2022) Expression of Tissue microRNAs in Ascending Aortic Aneurysms and Dissections, Angiology, 10.1177/00033197221098295, (000331972210982) October 24, 2014Vol 115, Issue 10 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.114.305233PMID: 25342766 Originally publishedOctober 24, 2014 Keywordsextracellular matrixmicroRNAsaortic aneurysm, abdominalEditorialsPDF download Advertisement SubjectsVascular Biology" @default.
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