Cited by 164Cardiac Fibrosis and RemodelingCardiomyopathy and Myosin StudiesCardiac electrophysiology and arrhythmias

Cardiac-specific deletion of LKB1 leads to hypertrophy and dysfunction

Open access
Ikeda, Yasumasa, Sato, Kaori, Pimentel, David R., Sam, Flora, Shaw, Reuben J., Dyck, Jason R.B., Walsh, Kenneth·2009·Journal of Biological Chemistry

Abstract

LKB1 encodes a serine/threonine kinase, which functions upstream of the AMP-activated protein kinase (AMPK) superfamily. To clarify the role of LKB1 in heart, we generated and characterized cardiac myocyte-specific LKB1 knock-out (KO) mice using alpha-myosin heavy chain-Cre deletor strain. LKB1-KO mice displayed biatrial enlargement with atrial fibrillation and cardiac dysfunction at 4 weeks of age. Left ventricular hypertrophy was observed in LKB1-KO mice at 12 weeks but not 4 weeks of age. Collagen I and III mRNA expression was elevated in atria at 4 weeks, and atrial fibrosis was seen at 12 weeks. LKB1-KO mice displayed cardiac dysfunction and atrial fibrillation and died within 6 months of age. Indicative of a prohypertrophic environment, the phosphorylation of AMPK and eEF2 was reduced, whereas mammalian target of rapamycin (mTOR) phosphorylation and p70S6 kinase phosphorylation were increased in both the atria and ventricles of LKB1-deficient mice. Consistent with vascular endothelial growth factor mRNA and protein levels being significantly reduced in LKB1-KO mice, these mice also exhibited a reduction in capillary density of both atria and ventricles. In cultured cardiac myocytes, LKB1 silencing induced hypertrophy, which was ameliorated by the expression of a constitutively active form AMPK or by treatment with the inhibitor of mTOR, rapamycin. These findings indicate that LKB1 signaling in cardiac myocytes is essential for normal development of the atria and ventricles. Cardiac hypertrophy and dysfunction in LKB1-deficient hearts are associated with alterations in AMPK and mTOR/p70S6 kinase/eEF2 signaling and with a reduction in vascular endothelial growth factor expression and vessel rarefaction.

Integrity signals

Registry

Crossref · 10.1074/jbc.m109.057273

Cites

55 of 55 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Ikeda, Y., Sato, K., Pimentel, D. R., Sam, F., Shaw, R. J., Dyck, J. R. B., & Walsh, K.
Affiliations
  • Boston University (US)
  • Salk Institute for Biological Studies (US)
  • University of Alberta (CA)
Corresponding author
Walsh, Kenneth
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2009-12
Volume
284
Issue
51
Pages
35839-35849
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2047392757
Cited by
164
References
55
Citations by year
2026: 6 · 2025: 7 · 2024: 6 · 2023: 7 · 2022: 10 · 2021: 11 · 2020: 10 · 2019: 10 · 2018: 11 · 2017: 9 · 2016: 11 · 2015: 15 · 2014: 13 · 2013: 6 · 2012: 12
FWCI
6.93
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Canadian Institutes of Health Research (MOP53088)
  • National Institute on Aging (R01AG015052, R37AG015052)
  • National Heart, Lung, and Blood Institute (R01HL086785, R01HL079099, R01HL077774, P01HL068758, HL 079099, R21HL095891)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
LKB1, cardiac hypertrophy, cardiac dysfunction, atrial fibrillation, atrial fibrosis, AMPK, mTOR signaling, p70 S6 kinase, elongation factor 2, vascular endothelial growth factor, capillary density, collagen expression, heart development
MeSH terms
AMP-Activated Protein Kinase Kinases, Animals, Antibiotics, Antineoplastic, Atrial Fibrillation, Carrier Proteins, Fibrosis, Gene Expression Regulation, Heart Atria, Myocardium, Organ Specificity, Phosphorylation, Protein Kinases, RNA, Messenger, Signal Transduction, Protein Serine-Threonine Kinases, Hypertrophy, Left Ventricular, Phosphotransferases (Alcohol Group Acceptor), Mice, Knockout, Sirolimus, Peptide Elongation Factor 2, Collagen Type I, Collagen Type II, Ribosomal Protein S6 Kinases, 70-kDa, Mice, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review