Expression of an active LKB1 complex in cardiac myocytes results in decreased protein synthesis associated with phenylephrine-induced hypertrophy.
AMP-activated protein kinase (AMPK) is a major metabolic regulator in the cardiac myocyte. Recently, LKB1 was identified as a kinase that regulates AMPK. Using immunoblot analysis, we confirmed high expression of LKB1 in isolated rat cardiac myocytes but show that, under basal conditions, LKB1 is primarily localized to the nucleus, where it is inactive. We examined the role of LKB1 in cardiac myocytes, using adenoviruses that express LKB1, and its binding partners Ste20-related adaptor protein (STRADalpha) and MO25alpha. Infection of neonatal rat cardiac myocytes with all three adenoviruses substantially increased LKB1/STRADalpha/MO25alpha expression, LKB1 activity, and AMPKalpha phosphorylation at its activating phosphorylation site (threonine-172). Since activation of AMPK can inhibit hypertrophic growth and since LKB1 is upstream of AMPK, we hypothesized that expression of an active LKB1 complex would also inhibit protein synthesis associated with hypertrophic growth. Expression of the LKB1/STRADalpha/MO25alpha complex in neonatal rat cardiac myocytes inhibited the increase in protein synthesis observed in cells treated with phenylephrine (measured via [(3)H]phenylalanine incorporation). This was associated with a decreased phosphorylation of p70S6 kinase and its substrate S6 ribosomal protein, key regulators of protein synthesis. In addition, we show that the pathological cardiac hypertrophy in transgenic mice with cardiac-specific expression of activated calcineurin is associated with a significant decrease in LKB1 expression. Together, our data show that increased LKB1 activity in the cardiac myocyte can decrease hypertrophy-induced protein synthesis and suggest that LKB1 activation may be a method for the prevention of pathological cardiac hypertrophy.
Noga
Anna A
AA
Cardiovascular Research Group, Department of Pediatrics, Faculty of Medicine and Dentistry, Univ of Alberta, Edmonton, Alberta, Canada.
Soltys
Carrie-Lynn M
CL
Barr
Amy J
AJ
Kovacic
Suzanne
S
Lopaschuk
Gary D
GD
Dyck
Jason R B
JR
D000091162:AMP-Activated Protein Kinase Kinases; D000256:Adenoviridae; D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D002478:Cells, Cultured; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010656:Phenylephrine; D010957:Plasmids; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D011994:Recombinant Proteins; D010656:Phenylephrine; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases