Cardiac-specific deletion of LKB1 leads to hypertrophy and dysfunction.
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.
Ikeda
Yasumasa
Y
Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Sato
Kaori
K
Pimentel
David R
DR
Sam
Flora
F
Shaw
Reuben J
RJ
Dyck
Jason R B
JR
Walsh
Kenneth
K
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D024043:Collagen Type II / Q000096:biosynthesis / Q000235:genetics; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006325:Heart Atria / Q000201:enzymology / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D020652:Peptide Elongation Factor 2 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D024042:Collagen Type I; D024043:Collagen Type II; D020652:Peptide Elongation Factor 2; D012333:RNA, Messenger; D011494:Protein Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D020123:Sirolimus