Cardiac-specific deletion of LKB1 leads to hypertrophy and dysfunction
Open accessAbstract
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.
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Cardiac LKB1 null mice are associated with hypertrophy.
“In parallel, cardiac LKB1 null mice are associated with hypertrophy [200].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [200]
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- 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)
- PMC
- PMC2791013
- 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
- hybrid
- doi.org
- Licence
- 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
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