Evidence map›Paper›PMID 33821665›Full record

ArticleCirculation2021

Systems Approach to Discovery of Therapeutic Targets for Vein Graft Disease: PPARα Pivotally Regulates Metabolism, Activation, and Heterogeneity of Macrophages and Lesion Development.

Julius L Decano, Sasha A Singh, Cauê Gasparotto Bueno, Lang Ho Lee, Arda Halu, Sarvesh Chelvanambi, Joan T Matamalas, Hengmin Zhang, Andrew K Mlynarchik, Jiao Qiao and 8 more

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

Article in Circulation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.

0numbers the graph read from it
0cells of the map it votes in
24citing 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

24 citing papers in PubMed, 38 citations in OpenAlex.

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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

18 authors at 2 institutions in 2 countries.

Julius L DecanoCenter for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (J.L.D., S.A.S., C.G.B., L.H.L., A.H., S.C., J.T.M., H.Z., A.K.M., J.Q., A.S., S.M., J.W., E.A., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Sasha A SinghCenter for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (J.L.D., S.A.S., C.G.B., L.H.L., A.H., S.C., J.T.M., H.Z., A.K.M., J.Q., A.S., S.M., J.W., E.A., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Cauê Gasparotto BuenoCenter for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (J.L.D., S.A.S., C.G.B., L.H.L., A.H., S.C., J.T.M., H.Z., A.K.M., J.Q., A.S., S.M., J.W., E.A., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Lang Ho LeeCenter for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (J.L.D., S.A.S., C.G.B., L.H.L., A.H., S.C., J.T.M., H.Z., A.K.M., J.Q., A.S., S.M., J.W., E.A., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Arda HaluCenter for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (J.L.D., S.A.S., C.G.B., L.H.L., A.H., S.C., J.T.M., H.Z., A.K.M., J.Q., A.S., S.M., J.W., E.A., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Sarvesh ChelvanambiCenter for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (J.L.D., S.A.S., C.G.B., L.H.L., A.H., S.C., J.T.M., H.Z., A.K.M., J.Q., A.S., S.M., J.W., E.A., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Joan T MatamalasCenter for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (J.L.D., S.A.S., C.G.B., L.H.L., A.H., S.C., J.T.M., H.Z., A.K.M., J.Q., A.S., S.M., J.W., E.A., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Hengmin ZhangCenter for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (J.L.D., S.A.S., C.G.B., L.H.L., A.H., S.C., J.T.M., H.Z., A.K.M., J.Q., A.S., S.M., J.W., E.A., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Andrew K MlynarchikCenter for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (J.L.D., S.A.S., C.G.B., L.H.L., A.H., S.C., J.T.M., H.Z., A.K.M., J.Q., A.S., S.M., J.W., E.A., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Jiao QiaoCenter for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (J.L.D., S.A.S., C.G.B., L.H.L., A.H., S.C., J.T.M., H.Z., A.K.M., J.Q., A.S., S.M., J.W., E.A., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Amitabh SharmaCenter for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (J.L.D., S.A.S., C.G.B., L.H.L., A.H., S.C., J.T.M., H.Z., A.K.M., J.Q., A.S., S.M., J.W., E.A., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Shin MukaiCenter for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (J.L.D., S.A.S., C.G.B., L.H.L., A.H., S.C., J.T.M., H.Z., A.K.M., J.Q., A.S., S.M., J.W., E.A., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Jianguo WangCenter for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (J.L.D., S.A.S., C.G.B., L.H.L., A.H., S.C., J.T.M., H.Z., A.K.M., J.Q., A.S., S.M., J.W., E.A., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Daniel G AndersonInstitutes for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge (D.G.A.).
C Keith OzakiDepartment of Medicine, Division of Vascular and Endovascular Surgery, Department of Surgery (C.K.O.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Peter LibbyCenter for Excellence in Vascular Biology (P.L., E.A., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Elena AikawaCenter for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (J.L.D., S.A.S., C.G.B., L.H.L., A.H., S.C., J.T.M., H.Z., A.K.M., J.Q., A.S., S.M., J.W., E.A., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Masanori AikawaCenter for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (J.L.D., S.A.S., C.G.B., L.H.L., A.H., S.C., J.T.M., H.Z., A.K.M., J.Q., A.S., S.M., J.W., E.A., M.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Brigham and Women's Hospital · USMassachusetts Institute of Technology · US

Funding

Pro-inflammatory activation of human macrophages regulated by lncRNAsR01HL149302 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI AIKAWA, MASANORI · 2019 to 2022
$2.9M
PARP9 and PARP14 in atherosclerosisR01HL126901 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI AIKAWA, MASANORI · 2016 to 2019
$2.4M
Dll4 in macrophage activationR01HL107550 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI AIKAWA, MASANORI · 2012 to 2015
$2.1M
NHLBI NIH HHS R01 HL107550NHLBI NIH HHS R01 HL126901NHLBI NIH HHS R01 HL149302
6 · The paper itself

Abstract

backgroundVein graft failure remains a common clinical challenge. We applied a systems approach in mouse experiments to discover therapeutic targets for vein graft failure.

methodsGlobal proteomics and high-dimensional clustering on multiple vein graft tissues were used to identify potential pathogenic mechanisms. The PPARs (peroxisome proliferator-activated receptors) pathway served as an example to substantiate our discovery platform. In vivo mouse experiments with macrophage-targeted PPARα small interfering RNA, or the novel, selective activator pemafibrate demonstrate the role of PPARα in the development and inflammation of vein graft lesions. In vitro experiments further included metabolomic profiling, quantitative polymerase chain reaction, flow cytometry, metabolic assays, and single-cell RNA sequencing on primary human and mouse macrophages.

resultsWe identified changes in the vein graft proteome associated with immune responses, lipid metabolism regulated by the PPARs, fatty acid metabolism, matrix remodeling, and hematopoietic cell mobilization. PPARα agonism by pemafibrate retarded the development and inflammation of vein graft lesions in mice, whereas gene silencing worsened plaque formation. Pemafibrate also suppressed arteriovenous fistula lesion development. Metabolomics/lipidomics, functional metabolic assays, and single-cell analysis of cultured human macrophages revealed that PPARα modulates macrophage glycolysis, citrate metabolism, mitochondrial membrane sphingolipid metabolism, and heterogeneity.

conclusionsThis study explored potential drivers of vein graft inflammation and identified PPARα as a novel potential pharmacological treatment for this unmet medical need.

Indexed as

Systems AnalysisAnimalsGraft SurvivalHumansLeukocytes, MononuclearMacrophagesMiceMice, Inbred C57BLMice, KnockoutPPAR alphaProteomicsVascular GraftingVena Cava, InferiorPPAR alphaarteriovenousfistulainflammationmacrophagepemafibrateproteomicssystems biologyvein graft

Identifiers

PMID33821665
PMCPMC8212880
OpenAlexW3151694332

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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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.