Evidence map›Paper›PMID 27312222›Full record

ArticleArteriosclerosis, thrombosis, and vascular biology2016

Cadherin-11 Overexpression Induces Extracellular Matrix Remodeling and Calcification in Mature Aortic Valves.

Derek C Sung, Caitlin J Bowen, Kiran A Vaidya, Jingjing Zhou, Nikita Chapurin, Andrew Recknagel, Bin Zhou, Jonathan Chen, Michael Kotlikoff, Jonathan T Butcher

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Article in Arteriosclerosis, thrombosis, and vascular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.

0numbers the graph read from it
0cells of the map it votes in
34citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

34 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors.

Derek C SungFrom the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Caitlin J BowenFrom the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Kiran A VaidyaFrom the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Jingjing ZhouFrom the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Nikita ChapurinFrom the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Andrew RecknagelFrom the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Bin ZhouFrom the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Jonathan ChenFrom the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Michael KotlikoffFrom the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Jonathan T ButcherFrom the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.). jtb47@cornell.edu.

Funding

DYNAMIC STUDIES OF COAGULATION AND THROMBOSISR01HL018672 · NHLBI · RICE UNIVERSITY · PI MC INTIRE, LARRY V. · 1985 to 2011
$3.5M
Molecular and Cellular Mechanisms of Calcific Aortic StenosisR01HL111770 · NHLBI · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI ZHOU, BIN · 2012 to 2015
$2.3M
TRANSCRIPTIONAL REGULATION OF ENDOCARDIAL DEVELOPMENTR01HL078881 · NHLBI · VANDERBILT UNIVERSITY · PI ZHOU, BIN · 2006 to 2010
$2.0M
Biomechanical regulation of valvulogenesisR01HL110328 · NHLBI · CORNELL UNIVERSITY · PI BUTCHER, JONATHAN TALBOT · 2011 to 2015
$1.9M
Adhesive signaling in aortic valve development and diseaseR01HL128745 · NHLBI · CORNELL UNIVERSITY · PI BUTCHER, JONATHAN TALBOT · 2015 to 2018
$1.5M
Acquisition of a VisualSonics Vevo 2100 mouse ultrasound for Cornell Imaging faciS10OD016191 · OD · CORNELL UNIVERSITY · PI WILLIAMS, REBECCA M · 2014 to 2014
$534k
Zeiss LSM710 Confocal Microscope for Shared Imaging FacilityS10RR025502 · NCRR · CORNELL UNIVERSITY · PI WILLIAMS, REBECCA M · 2009 to 2009
$500k
Mouse Model of Human Calcific Aortic Valve StenosisR21HL104444 · NHLBI · ALBERT EINSTEIN COLLEGE OF MEDICINE · PI ZHOU, BIN · 2010 to 2011
$457k
Effects of hydroxyapatite mineralization and valve cell phenotypeR21HL118672 · NHLBI · CORNELL UNIVERSITY · PI BUTCHER, JONATHAN TALBOT · 2013 to 2014
$405k
DYNAMIC STUDIES OF COAGULATION AND THROMBOSISR37HL018672 · NHLBI · RICE UNIVERSITY · PI MC INTIRE, LARRY V. · 1990 to 1999
–
NCRR NIH HHS S10 RR025502NHLBI NIH HHS R01 HL018672NHLBI NIH HHS R01 HL078881NHLBI NIH HHS R01 HL110328NHLBI NIH HHS R01 HL111770NHLBI NIH HHS R01 HL128745NHLBI NIH HHS R21 HL104444NHLBI NIH HHS R21 HL118672NHLBI NIH HHS R37 HL018672NIH HHS S10 OD016191
6 · The paper itself

Abstract

objectiveCalcific aortic valve (AoV) disease is a significant clinical problem for which the regulatory mechanisms are poorly understood. Enhanced cell-cell adhesion is a common mechanism of cellular aggregation, but its role in calcific lesion formation is not known. Cadherin-11 (Cad-11) has been associated with lesion formation in vitro, but its function during adult valve homeostasis and pathogenesis is not known. This study aims to elucidate the specific functions of Cad-11 and its downstream targets, RhoA and Sox9, in extracellular matrix remodeling and AoV calcification. APPROACH AND

resultsWe conditionally overexpressed Cad-11 in murine heart valves using a novel double-transgenic Nfatc1(Cre);R26-Cad11(TglTg) mouse model. These mice developed hemodynamically significant aortic stenosis with prominent calcific lesions in the AoV leaflets. Cad-11 overexpression upregulated downstream targets, RhoA and Sox9, in the valve interstitial cells, causing calcification and extensive pathogenic extracellular matrix remodeling. AoV interstitial cells overexpressing Cad-11 in an osteogenic environment in vitro rapidly form calcific nodules analogous to in vivo lesions. Molecular analyses revealed upregulation of osteoblastic and myofibroblastic markers. Treatment with a Rho-associated protein kinase inhibitor attenuated nodule formation, further supporting that Cad-11-driven calcification acts through the small GTPase RhoA/Rho-associated protein kinase signaling pathway.

conclusionsThis study identifies one of the underlying molecular mechanisms of heart valve calcification and demonstrates that overexpression of Cad-11 upregulates RhoA and Sox9 to induce calcification and extracellular matrix remodeling in adult AoV pathogenesis. The findings provide a potential molecular target for clinical treatment.

Indexed as

AnimalsAortic ValveAortic Valve StenosisCadherinsCalcinosisCase-Control StudiesCell AdhesionCell MovementCells, CulturedDisease Models, AnimalExtracellular MatrixGenetic Predisposition to DiseaseHumansMice, Inbred C57BLMice, TransgenicPhenotypeCadherinsosteoblast cadherinrhoA GTP-Binding ProteinRHOA protein, humanRhoA protein, mouserho-Associated Kinasesrho GTP-Binding ProteinsSOX9 protein, humanSox9 protein, mouseSOX9 Transcription Factoraortic valvecadherincell adhesionextracellular matrixstenosis

Identifiers

PMID27312222
PMCPMC4965289

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.