Cardiac-specific deletion of LKB1 leads to hypertrophy and dysfunction

J Biol Chem. 2009 Dec 18;284(51):35839-49. doi: 10.1074/jbc.M109.057273.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Atrial Fibrillation / enzymology*
  • Atrial Fibrillation / genetics
  • Atrial Fibrillation / pathology
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Collagen Type I / biosynthesis
  • Collagen Type I / genetics
  • Collagen Type II / biosynthesis
  • Collagen Type II / genetics
  • Fibrosis
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Heart Atria / enzymology
  • Heart Atria / pathology
  • Hypertrophy, Left Ventricular / enzymology*
  • Hypertrophy, Left Ventricular / genetics
  • Hypertrophy, Left Ventricular / pathology
  • Mice
  • Mice, Knockout
  • Myocardium / enzymology*
  • Myocardium / pathology
  • Organ Specificity / genetics
  • Peptide Elongation Factor 2 / genetics
  • Peptide Elongation Factor 2 / metabolism
  • Phosphorylation / drug effects
  • Phosphorylation / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases

Substances

  • Antibiotics, Antineoplastic
  • Carrier Proteins
  • Collagen Type I
  • Collagen Type II
  • Peptide Elongation Factor 2
  • RNA, Messenger
  • Protein Kinases
  • AMP-activated protein kinase kinase
  • Phosphotransferases (Alcohol Group Acceptor)
  • Stk11 protein, mouse
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Protein-Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Sirolimus