Evidence map›Paper›PMID 26966280›Full record

ArticleArteriosclerosis, thrombosis, and vascular biology2016

Leukocyte Calpain Deficiency Reduces Angiotensin II-Induced Inflammation and Atherosclerosis But Not Abdominal Aortic Aneurysms in Mice.

Deborah A Howatt, Anju Balakrishnan, Jessica J Moorleghen, Latha Muniappan, Debra L Rateri, Haruhito A Uchida, Jiro Takano, Takaomi C Saido, Athar H Chishti, Laurent Baud and 1 more

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

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 21 papers.

0numbers the graph read from it
0cells of the map it votes in
21citing papers in PubMed
4.0field-weighted citation impact, top 7% 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

21 citing papers in PubMed, 36 citations in OpenAlex.

  1. Calpain-2-Mediated Endothelial Focal Adhesion Disruption in Thoracic Aortic Dissection.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025
    Article
  2. Review
  3. Article
  4. Review
  5. Inducible Depletion of Calpain-2 Mitigates Abdominal Aortic Aneurysm in Mice.Arteriosclerosis, thrombosis, and vascular biology · 2021
    Article
  6. Article
  7. Article
  8. Article
  9. Article
  10. Reporting Sex and Sex Differences in Preclinical Studies.Arteriosclerosis, thrombosis, and vascular biology · 2018
    Article
  11. Review
  12. Renin-Angiotensin System and Cardiovascular Functions.Arteriosclerosis, thrombosis, and vascular biology · 2018
    Review
  13. Article
  14. Review
  15. Article
  16. Article
  17. Article
  18. Review
  19. Aortic Aneurysms.Arteriosclerosis, thrombosis, and vascular biology · 2017
    Review
  20. Review
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

11 authors at 3 institutions in 2 countries.

Deborah A HowattFrom the Saha Cardiovascular Research Center (D.A.H., A.B., J.J.M., L.M., D.L.R.), and Department of Physiology (V.S.), University of Kentucky, Lexington; Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan (H.A.U.); Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan (J.T., T.C.S.); Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA (A.H.C.); and INSERM, Université Pierre et Marie Curie-Paris, Paris, France (L.B.).
Anju BalakrishnanFrom the Saha Cardiovascular Research Center (D.A.H., A.B., J.J.M., L.M., D.L.R.), and Department of Physiology (V.S.), University of Kentucky, Lexington; Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan (H.A.U.); Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan (J.T., T.C.S.); Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA (A.H.C.); and INSERM, Université Pierre et Marie Curie-Paris, Paris, France (L.B.).
Jessica J MoorleghenFrom the Saha Cardiovascular Research Center (D.A.H., A.B., J.J.M., L.M., D.L.R.), and Department of Physiology (V.S.), University of Kentucky, Lexington; Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan (H.A.U.); Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan (J.T., T.C.S.); Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA (A.H.C.); and INSERM, Université Pierre et Marie Curie-Paris, Paris, France (L.B.).
Latha MuniappanFrom the Saha Cardiovascular Research Center (D.A.H., A.B., J.J.M., L.M., D.L.R.), and Department of Physiology (V.S.), University of Kentucky, Lexington; Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan (H.A.U.); Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan (J.T., T.C.S.); Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA (A.H.C.); and INSERM, Université Pierre et Marie Curie-Paris, Paris, France (L.B.).
Debra L RateriFrom the Saha Cardiovascular Research Center (D.A.H., A.B., J.J.M., L.M., D.L.R.), and Department of Physiology (V.S.), University of Kentucky, Lexington; Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan (H.A.U.); Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan (J.T., T.C.S.); Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA (A.H.C.); and INSERM, Université Pierre et Marie Curie-Paris, Paris, France (L.B.).
Haruhito A UchidaFrom the Saha Cardiovascular Research Center (D.A.H., A.B., J.J.M., L.M., D.L.R.), and Department of Physiology (V.S.), University of Kentucky, Lexington; Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan (H.A.U.); Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan (J.T., T.C.S.); Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA (A.H.C.); and INSERM, Université Pierre et Marie Curie-Paris, Paris, France (L.B.).
Jiro TakanoFrom the Saha Cardiovascular Research Center (D.A.H., A.B., J.J.M., L.M., D.L.R.), and Department of Physiology (V.S.), University of Kentucky, Lexington; Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan (H.A.U.); Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan (J.T., T.C.S.); Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA (A.H.C.); and INSERM, Université Pierre et Marie Curie-Paris, Paris, France (L.B.).
Takaomi C SaidoFrom the Saha Cardiovascular Research Center (D.A.H., A.B., J.J.M., L.M., D.L.R.), and Department of Physiology (V.S.), University of Kentucky, Lexington; Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan (H.A.U.); Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan (J.T., T.C.S.); Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA (A.H.C.); and INSERM, Université Pierre et Marie Curie-Paris, Paris, France (L.B.).
Athar H ChishtiFrom the Saha Cardiovascular Research Center (D.A.H., A.B., J.J.M., L.M., D.L.R.), and Department of Physiology (V.S.), University of Kentucky, Lexington; Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan (H.A.U.); Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan (J.T., T.C.S.); Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA (A.H.C.); and INSERM, Université Pierre et Marie Curie-Paris, Paris, France (L.B.).
Laurent BaudFrom the Saha Cardiovascular Research Center (D.A.H., A.B., J.J.M., L.M., D.L.R.), and Department of Physiology (V.S.), University of Kentucky, Lexington; Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan (H.A.U.); Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan (J.T., T.C.S.); Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA (A.H.C.); and INSERM, Université Pierre et Marie Curie-Paris, Paris, France (L.B.).
Venkateswaran SubramanianFrom the Saha Cardiovascular Research Center (D.A.H., A.B., J.J.M., L.M., D.L.R.), and Department of Physiology (V.S.), University of Kentucky, Lexington; Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan (H.A.U.); Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan (J.T., T.C.S.); Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA (A.H.C.); and INSERM, Université Pierre et Marie Curie-Paris, Paris, France (L.B.). venkat.subramanian@uky.edu.
RIKEN Center for Brain Science · JPOkayama University · JPTufts University · US

Funding

WU P&FP30DK020579 · NIDDK · WASHINGTON UNIVERSITY · PI Irfan J Lodhi · 2013 to 2026
$27.1M
The role of IKKß in linking obesity to adipose tissue inflammation and adipogeneP20GM103527 · NIGMS · UNIVERSITY OF KENTUCKY · PI CASSIS, LISA A · 2012 to 2017
$13.7M
THROMBOSPONDIN1 MEDIATES MACROPHAGE INFILTRATION INTO ADIPOSE TISSUE AND PROMOTEP20RR021954 · NCRR · UNIVERSITY OF KENTUCKY · PI ECKHARDT, ERIK · 2008 to 2011
$8.3M
Calpain-1 Signaling Pathways in PlateletsR01HL089517 · NHLBI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI CHISHTI, ATHAR H. · 2009 to 2012
$1.6M
NCRR NIH HHS P20 RR021954NHLBI NIH HHS R01 HL089517NIDDK NIH HHS P30 DK020579NIGMS NIH HHS P20 GM103527
6 · The paper itself

Abstract

objectiveAngiotensin II (AngII) infusion profoundly increases activity of calpains, calcium-dependent neutral cysteine proteases, in mice. Pharmacological inhibition of calpains attenuates AngII-induced aortic medial macrophage accumulation, atherosclerosis, and abdominal aortic aneurysm in mice. However, the precise functional contribution of leukocyte-derived calpains in AngII-induced vascular pathologies has not been determined. The purpose of this study was to determine whether calpains expressed in bone marrow (BM)-derived cells contribute to AngII-induced atherosclerosis and aortic aneurysms in hypercholesterolemic mice. APPROACH AND

resultsTo study whether leukocyte calpains contributed to AngII-induced aortic pathologies, irradiated male low-density lipoprotein receptor(-/-) mice were repopulated with BM-derived cells that were either wild-type or overexpressed calpastatin, the endogenous inhibitor of calpains. Mice were fed a fat-enriched diet and infused with AngII (1000 ng/kg per minute) for 4 weeks. Overexpression of calpastatin in BM-derived cells significantly attenuated AngII-induced atherosclerotic lesion formation in aortic arches, but had no effect on aneurysm formation. Using either BM-derived cells from calpain-1-deficient mice or mice with leukocyte-specific calpain-2 deficiency generated using cre-loxP recombination technology, further studies demonstrated that independent deficiency of either calpain-1 or -2 in leukocytes modestly attenuated AngII-induced atherosclerosis. Calpastatin overexpression significantly attenuated AngII-induced inflammatory responses in macrophages and spleen. Furthermore, calpain inhibition suppressed migration and adhesion of macrophages to endothelial cells in vitro. Calpain inhibition also significantly decreased hypercholesterolemia-induced atherosclerosis in the absence of AngII.

conclusionsThe present study demonstrates a pivotal role for BM-derived calpains in mediating AngII-induced atherosclerosis by influencing macrophage function.

Indexed as

Angiotensin IIAnimalsAortic Aneurysm, AbdominalAtherosclerosisBone Marrow TransplantationCalcium-Binding ProteinsCalpainCell AdhesionCell MovementCells, CulturedCoculture TechniquesCysteine Proteinase InhibitorsDiet, High-FatDisease Models, AnimalEndothelial CellsGenetic Predisposition to DiseaseAngiotensin IICalcium-Binding ProteinsCalpaincalpastatinCapn1 protein, mouseCapn2 protein, mouseCysteine Proteinase InhibitorsReceptors, LDLangiotensin IIatherosclerosiscalpaininflammationmacrophages

Identifiers

PMID26966280
PMCPMC4850100
OpenAlexW2294568732

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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.