Evidence map›Paper›PMID 26034040›Full record

ArticleCirculation research2015

Vascular smooth muscle LRP6 limits arteriosclerotic calcification in diabetic LDLR-/- mice by restraining noncanonical Wnt signals.

Su-Li Cheng, Bindu Ramachandran, Abraham Behrmann, Jian-Su Shao, Megan Mead, Carolyn Smith, Karen Krchma, Yoanna Bello Arredondo, Attila Kovacs, Kapil Kapoor and 4 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.

0numbers the graph read from it
0cells of the map it votes in
64citing papers in PubMed
4.2field-weighted citation impact, top 5% of its field
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

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

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

64 citing papers in PubMed, 92 citations in OpenAlex.

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  8. Genes & diseases · 2024
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  16. Histone modification in podocyte injury of diabetic nephropathy.Journal of molecular medicine (Berlin, Germany) · 2022
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4 more citing papers are in PubMed but not listed here.

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

14 authors at 2 institutions in 1 country.

Su-Li ChengFrom the Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Cardiovascular Pathobiology, Orlando, FL (S.-L.C., B.R., A.B., M.M., C.S., Y.B.A., K.K., L.M.B., R.P., D.A.T.); MD Anderson Cancer Center, Cancer Biology, Houston, TX (J.-S.S.); Washington University, Department of Medicine, St. Louis, MO (K.K., A.K.); and Van Andel Research Institute, Department of Cancer and Cell Biology, Grand Rapids, MI (B.O.W.).
Bindu RamachandranFrom the Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Cardiovascular Pathobiology, Orlando, FL (S.-L.C., B.R., A.B., M.M., C.S., Y.B.A., K.K., L.M.B., R.P., D.A.T.); MD Anderson Cancer Center, Cancer Biology, Houston, TX (J.-S.S.); Washington University, Department of Medicine, St. Louis, MO (K.K., A.K.); and Van Andel Research Institute, Department of Cancer and Cell Biology, Grand Rapids, MI (B.O.W.).
Abraham BehrmannFrom the Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Cardiovascular Pathobiology, Orlando, FL (S.-L.C., B.R., A.B., M.M., C.S., Y.B.A., K.K., L.M.B., R.P., D.A.T.); MD Anderson Cancer Center, Cancer Biology, Houston, TX (J.-S.S.); Washington University, Department of Medicine, St. Louis, MO (K.K., A.K.); and Van Andel Research Institute, Department of Cancer and Cell Biology, Grand Rapids, MI (B.O.W.).
Jian-Su ShaoFrom the Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Cardiovascular Pathobiology, Orlando, FL (S.-L.C., B.R., A.B., M.M., C.S., Y.B.A., K.K., L.M.B., R.P., D.A.T.); MD Anderson Cancer Center, Cancer Biology, Houston, TX (J.-S.S.); Washington University, Department of Medicine, St. Louis, MO (K.K., A.K.); and Van Andel Research Institute, Department of Cancer and Cell Biology, Grand Rapids, MI (B.O.W.).
Megan MeadFrom the Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Cardiovascular Pathobiology, Orlando, FL (S.-L.C., B.R., A.B., M.M., C.S., Y.B.A., K.K., L.M.B., R.P., D.A.T.); MD Anderson Cancer Center, Cancer Biology, Houston, TX (J.-S.S.); Washington University, Department of Medicine, St. Louis, MO (K.K., A.K.); and Van Andel Research Institute, Department of Cancer and Cell Biology, Grand Rapids, MI (B.O.W.).
Carolyn SmithFrom the Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Cardiovascular Pathobiology, Orlando, FL (S.-L.C., B.R., A.B., M.M., C.S., Y.B.A., K.K., L.M.B., R.P., D.A.T.); MD Anderson Cancer Center, Cancer Biology, Houston, TX (J.-S.S.); Washington University, Department of Medicine, St. Louis, MO (K.K., A.K.); and Van Andel Research Institute, Department of Cancer and Cell Biology, Grand Rapids, MI (B.O.W.).
Karen KrchmaFrom the Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Cardiovascular Pathobiology, Orlando, FL (S.-L.C., B.R., A.B., M.M., C.S., Y.B.A., K.K., L.M.B., R.P., D.A.T.); MD Anderson Cancer Center, Cancer Biology, Houston, TX (J.-S.S.); Washington University, Department of Medicine, St. Louis, MO (K.K., A.K.); and Van Andel Research Institute, Department of Cancer and Cell Biology, Grand Rapids, MI (B.O.W.).
Yoanna Bello ArredondoFrom the Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Cardiovascular Pathobiology, Orlando, FL (S.-L.C., B.R., A.B., M.M., C.S., Y.B.A., K.K., L.M.B., R.P., D.A.T.); MD Anderson Cancer Center, Cancer Biology, Houston, TX (J.-S.S.); Washington University, Department of Medicine, St. Louis, MO (K.K., A.K.); and Van Andel Research Institute, Department of Cancer and Cell Biology, Grand Rapids, MI (B.O.W.).
Attila KovacsFrom the Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Cardiovascular Pathobiology, Orlando, FL (S.-L.C., B.R., A.B., M.M., C.S., Y.B.A., K.K., L.M.B., R.P., D.A.T.); MD Anderson Cancer Center, Cancer Biology, Houston, TX (J.-S.S.); Washington University, Department of Medicine, St. Louis, MO (K.K., A.K.); and Van Andel Research Institute, Department of Cancer and Cell Biology, Grand Rapids, MI (B.O.W.).
Kapil KapoorFrom the Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Cardiovascular Pathobiology, Orlando, FL (S.-L.C., B.R., A.B., M.M., C.S., Y.B.A., K.K., L.M.B., R.P., D.A.T.); MD Anderson Cancer Center, Cancer Biology, Houston, TX (J.-S.S.); Washington University, Department of Medicine, St. Louis, MO (K.K., A.K.); and Van Andel Research Institute, Department of Cancer and Cell Biology, Grand Rapids, MI (B.O.W.).
Laurence M BrillFrom the Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Cardiovascular Pathobiology, Orlando, FL (S.-L.C., B.R., A.B., M.M., C.S., Y.B.A., K.K., L.M.B., R.P., D.A.T.); MD Anderson Cancer Center, Cancer Biology, Houston, TX (J.-S.S.); Washington University, Department of Medicine, St. Louis, MO (K.K., A.K.); and Van Andel Research Institute, Department of Cancer and Cell Biology, Grand Rapids, MI (B.O.W.).
Ranjan PereraFrom the Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Cardiovascular Pathobiology, Orlando, FL (S.-L.C., B.R., A.B., M.M., C.S., Y.B.A., K.K., L.M.B., R.P., D.A.T.); MD Anderson Cancer Center, Cancer Biology, Houston, TX (J.-S.S.); Washington University, Department of Medicine, St. Louis, MO (K.K., A.K.); and Van Andel Research Institute, Department of Cancer and Cell Biology, Grand Rapids, MI (B.O.W.).
Bart O WilliamsFrom the Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Cardiovascular Pathobiology, Orlando, FL (S.-L.C., B.R., A.B., M.M., C.S., Y.B.A., K.K., L.M.B., R.P., D.A.T.); MD Anderson Cancer Center, Cancer Biology, Houston, TX (J.-S.S.); Washington University, Department of Medicine, St. Louis, MO (K.K., A.K.); and Van Andel Research Institute, Department of Cancer and Cell Biology, Grand Rapids, MI (B.O.W.).
Dwight A TowlerFrom the Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Cardiovascular Pathobiology, Orlando, FL (S.-L.C., B.R., A.B., M.M., C.S., Y.B.A., K.K., L.M.B., R.P., D.A.T.); MD Anderson Cancer Center, Cancer Biology, Houston, TX (J.-S.S.); Washington University, Department of Medicine, St. Louis, MO (K.K., A.K.); and Van Andel Research Institute, Department of Cancer and Cell Biology, Grand Rapids, MI (B.O.W.). dwight.towler@utsouthwestern.edu.
The University of Texas MD Anderson Cancer Center · USWashington University in St. Louis · US

Funding

OSTEOGENIC REGULATION OF VASCULAR CALCIFICATIONR01HL069229 · NHLBI · WASHINGTON UNIVERSITY · PI TOWLER, DWIGHT A. · 2001 to 2022
$7.9M
Analyzing the Role of Wnt Signaling in Bone DevelopmentR01AR053293 · NIAMS · VAN ANDEL RESEARCH INSTITUTE · PI WILLIAMS, BART O · 2007 to 2016
$4.0M
MSX2-WNT SIGNALING IN CARDIOVASCULAR CALCIFICATIONR01HL081138 · NHLBI · WASHINGTON UNIVERSITY · PI TOWLER, DWIGHT A. · 2005 to 2013
$3.4M
Endocrine Regulation of Calcific Aortic Valve Sclerosis: PTH/PTHRP Receptor SignaR01HL114806 · NHLBI · WASHINGTON UNIVERSITY · PI TOWLER, DWIGHT A. · 2012 to 2016
$2.1M
NHLBI NIH HHS HL069229NHLBI NIH HHS HL081138NHLBI NIH HHS HL114806NHLBI NIH HHS R01 HL069229NHLBI NIH HHS R01 HL081138NHLBI NIH HHS R01 HL114806NIAMS NIH HHS AR053292NIAMS NIH HHS R01 AR053293
6 · The paper itself

Abstract

rationaleWnt signaling regulates key aspects of diabetic vascular disease.

objectiveWe generated SM22-Cre;LRP6(fl/fl);LDLR(-/-) mice to determine contributions of Wnt coreceptor low-density lipoprotein receptor-related protein 6 (LRP6) in the vascular smooth muscle lineage of male low-density lipoprotein receptor-null mice, a background susceptible to diet (high-fat diet)-induced diabetic arteriosclerosis. METHODS AND

resultsAs compared with LRP6(fl/fl);LDLR(-/-) controls, SM22-Cre;LRP6(fl/fl);LDLR(-/-) (LRP6-VKO) siblings exhibited increased aortic calcification on high-fat diet without changes in fasting glucose, lipids, or body composition. Pulse wave velocity (index of arterial stiffness) was also increased. Vascular calcification paralleled enhanced aortic osteochondrogenic programs and circulating osteopontin (OPN), a matricellular regulator of arteriosclerosis. Survey of ligands and Frizzled (Fzd) receptor profiles in LRP6-VKO revealed upregulation of canonical and noncanonical Wnts alongside Fzd10. Fzd10 stimulated noncanonical signaling and OPN promoter activity via an upstream stimulatory factor (USF)-activated cognate inhibited by LRP6. RNA interference revealed that USF1 but not USF2 supports OPN expression in LRP6-VKO vascular smooth muscle lineage, and immunoprecipitation confirmed increased USF1 association with OPN chromatin. ML141, an antagonist of cdc42/Rac1 noncanonical signaling, inhibited USF1 activation, osteochondrogenic programs, alkaline phosphatase, and vascular smooth muscle lineage calcification. Mass spectrometry identified LRP6 binding to protein arginine methyltransferase (PRMT)-1, and nuclear asymmetrical dimethylarginine modification was increased with LRP6-VKO. RNA interference demonstrated that PRMT1 inhibits OPN and TNAP, whereas PRMT4 supports expression. USF1 complexes containing the histone H3 asymmetrically dimethylated on Arg-17 signature of PRMT4 are increased with LRP6-VKO. Jmjd6, a demethylase downregulated with LRP6 deficiency, inhibits OPN and TNAP expression, USF1: histone H3 asymmetrically dimethylated on Arg-17 complex formation, and transactivation.

conclusionsLRP6 restrains vascular smooth muscle lineage noncanonical signals that promote osteochondrogenic differentiation, mediated in part via USF1- and arginine methylation-dependent relays.

Indexed as

Wnt Signaling PathwayAnimalsArginineArteriosclerosisCalcinosisDiabetes Mellitus, ExperimentalDietary FatsFrizzled ReceptorsGene Expression RegulationHistonesLow Density Lipoprotein Receptor-Related Protein-6MaleMiceMice, KnockoutMuscle, Smooth, VascularMyocytes, Smooth MuscleArginineDietary FatsFrizzled ReceptorsFzd10 protein, mouseHistonesLow Density Lipoprotein Receptor-Related Protein-6Lrp6 protein, mouseN,N-dimethylarginineOsteopontinPrmt1 protein, mouseProtein-Arginine N-MethyltransferasesPtdsr protein, mouseReceptors, Cell SurfaceReceptors, LDLSpp1 protein, mouseUpstream Stimulatory FactorsUsf1 protein, mousearteriosclerosisLRP6signal transductiontype 2 diabetes mellitusUSF1vascular calcificationWnt

Identifiers

PMID26034040
PMCPMC4490945
OpenAlexW1899440446

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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.