The microRNA-15 family inhibits the TGFβ-pathway in the heart

被引：164

作者：

Tijsen, Anke J. ^{[1
]}

van der Made, Ingeborg ^{[1
]}

van den Hoogenhof, Maarten M. ^{[1
]}

Wijnen, Wino J. ^{[1
]}

van Deel, Elza D. ^{[2
]}

de Groot, Nina E. ^{[1
]}

Alekseev, Sergey ^{[1
]}

Fluiter, Kees ^{[3
]}

Schroen, Blanche ^{[4
]}

Goumans, Marie-Jose ^{[5
]}

van der Velden, Jolanda ^{[6
]}

Duncker, Dirk J. ^{[2
]}

Pinto, Yigal M. ^{[1
]}

Creemers, Esther E. ^{[1
]}

机构：

[1] Univ Amsterdam, Acad Med Ctr, Dept Expt Cardiol, NL-1105 AZ Amsterdam, Netherlands

[2] Univ Med Ctr Rotterdam, Dept Cardiol, Erasmus Med Ctr, Thoraxctr, Rotterdam, Netherlands

[3] Univ Amsterdam, Acad Med Ctr, Dept Genome Anal, NL-1105 AZ Amsterdam, Netherlands

[4] Maastricht Univ, Dept Cardiol, Ctr Heart Failure Res, Cardiovasc Res Inst Maastricht, Maastricht, Netherlands

[5] Leiden Univ, Dept Mol & Cell Biol, Ctr Biomed Genet, Med Ctr, Leiden, Netherlands

[6] Vrije Univ Amsterdam, Inst Cardiovasc Res, Physiol Lab, Med Ctr, Amsterdam, Netherlands

来源：

CARDIOVASCULAR RESEARCH | 2014年 / 104卷 / 01期

关键词：

Fibrosis; Hypertrophy; miRNA-15; family; TGF beta-pathway; LEFT-VENTRICULAR FIBROSIS; PRESSURE-OVERLOAD; MYOCARDIAL FIBROSIS; CARDIAC-HYPERTROPHY; IMPROVES SURVIVAL; GENE-EXPRESSION; TRANSGENIC MICE; MIR-15; FAMILY; FAILURE; TGF-BETA(1);

D O I：

10.1093/cvr/cvu184

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aims The overloaded heart remodels by cardiomyocyte hypertrophy and interstitial fibrosis, which contributes to the development of heart failure. Signalling via the TGF beta-pathway is crucial for this remodelling. Here we tested the hypothesis that microRNAs in the overloaded heart regulate this remodelling process via inhibition of the TGFb-pathway. Methods and results We show that the miRNA-15 family, which we found to be up-regulated in the overloaded heart in multiple species, inhibits the TGFb-pathway by targeting of TGFBR1 and several other genes within this pathway directly or indirectly, including p38, SMAD3, SMAD7, and endoglin. Inhibition of miR-15b by subcutaneous injections of LNA-based antimiRs in C57BL/6 mice subjected to transverse aorta constriction aggravated fibrosis and to a lesser extent also hypertrophy. Conclusion We identified the miR-15 family as a novel regulator of cardiac hypertrophy and fibrosis acting by inhibition of the TGF beta-pathway.

引用

页码：61 / 71

页数：11

共 30 条

[1] THE TGF-BETA SUPERFAMILY IN MYOCARDIUM - LIGANDS, RECEPTORS, TRANSDUCTION, AND FUNCTION [J].

BRAND, T ;

SCHNEIDER, MD .

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 1995, 27 (01) :5-18

[2] Myocardial fibrosis in transforming growth factor β1 heterozygous mice [J].

Brooks, WW ;

Conrad, CH .

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2000, 32 (02) :187-195

[3] miR-15 and miR-16 induce apoptosis by targeting BCL2 [J].

Cimmino, A ;

Calin, GA ;

Fabbri, M ;

Iorio, MV ;

Ferracin, M ;

Shimizu, M ;

Wojcik, SE ;

Aqeilan, RI ;

Zupo, S ;

Dono, M ;

Rassenti, L ;

Alder, H ;

Volinia, S ;

Liu, CG ;

Kipps, TJ ;

Negrini, M ;

Croce, CM .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (39) :13944-13949

[4] Direct binding of Smad3 and Smad4 to critical TGFβ-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene [J].

Dennler, S ;

Itoh, S ;

Vivien, D ;

ten Dijke, P ;

Huet, S ;

Gauthier, JM .

EMBO JOURNAL, 1998, 17 (11) :3091-3100

[5] Adaptive and Maladptive Effects of SMAD3 Signaling in the Adult Heart After Hemodynamic Pressure Overloading [J].

Divakaran, Vijay ;

Adrogue, Julia ;

Ishiyama, Masakuni ;

Entman, Mark L. ;

Haudek, Sandra ;

Sivasubramanian, Natarajan ;

Mann, Douglas L. .

CIRCULATION-HEART FAILURE, 2009, 2 (06) :633-U150

[6] miR-133 and miR-30 Regulate Connective Tissue Growth Factor Implications for a Role of MicroRNAs in Myocardial Matrix Remodeling [J].

Duisters, Rudy F. ;

Tijsen, Anke J. ;

Schroen, Blanche ;

Leenders, Joost J. ;

Lentink, Viola ;

van der Made, Ingeborg ;

Herias, Veronica ;

van Leeuwen, Rick E. ;

Schellings, Mark W. ;

Barenbrug, Paul ;

Maessen, Jos G. ;

Heymans, Stephane ;

Pinto, Yigal M. ;

Creemers, Esther E. .

CIRCULATION RESEARCH, 2009, 104 (02) :170-U61

[7] Inhibition of left ventricular fibrosis by tranilast in rats with renovascular hypertension [J].

Hocher, B ;

Godes, M ;

Olivier, J ;

Weil, J ;

Eschenhagen, T ;

Slowinski, T ;

Neumayer, HH ;

Bauer, C ;

Paul, M ;

Pinto, YM .

JOURNAL OF HYPERTENSION, 2002, 20 (04) :745-751

[8] Results of prevention of restenosis with tranilast and its outcomes (PRESTO) trial [J].

Holmes, DR ;

Savage, M ;

LaBlanche, JM ;

Grip, L ;

Serruys, PW ;

Fitzgerald, P ;

Fischman, D ;

Goldberg, S ;

Brinker, JA ;

Zeiher, AM ;

Shapiro, LM ;

Willerson, J ;

Davis, BR ;

Ferguson, JJ ;

Popma, J ;

King, SB ;

Lincoff, AM ;

Tcheng, JE ;

Chan, R ;

Granett, JR .

CIRCULATION, 2002, 106 (10) :1243-1250

[9] Inhibition of miR-15 Protects Against Cardiac Ischemic Injury [J].

Hullinger, Thomas G. ;

Montgomery, Rusty L. ;

Seto, Anita G. ;

Dickinson, Brent A. ;

Semus, Hillary M. ;

Lynch, Joshua M. ;

Dalby, Christina M. ;

Robinson, Kathryn ;

Stack, Christianna ;

Latimer, Paul A. ;

Hare, Joshua M. ;

Olson, Eric N. ;

van Rooij, Eva .

CIRCULATION RESEARCH, 2012, 110 (01) :71-81

[10] Treatment of HCV Infection by Targeting MicroRNA [J].

Janssen, Harry L. A. ;

Reesink, Hendrik W. ;

Lawitz, Eric J. ;

Zeuzem, Stefan ;

Rodriguez-Torres, Maribel ;

Patel, Keyur ;

van der Meer, Adriaan J. ;

Patick, Amy K. ;

Chen, Alice ;

Zhou, Yi ;

Persson, Robert ;

King, Barney D. ;

Kauppinen, Sakari ;

Levin, Arthur A. ;

Hodges, Michael R. .

NEW ENGLAND JOURNAL OF MEDICINE, 2013, 368 (18) :1685-1694

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