Role of heterotrimeric G protein and calcium in cardiomyocyte hypertrophy induced by IGF-1.
In the heart, insulin-like growth factor-1 (IGF-1) is a peptide with pro-hypertrophic and anti-apoptotic actions. The pro-hypertrophic properties of IGF-1 have been attributed to the extracellular regulated kinase (ERK) pathway. Recently, we reported that IGF-1 also increases intracellular Ca(2+) levels through a pertussis toxin (PTX)-sensitive G protein. Here we investigate whether this Ca(2+) signal is involved in IGF-1-induced cardiomyocyte hypertrophy. Our results show that the IGF-1-induced increase in Ca(2+) level is abolished by the IGF-1 receptor tyrosine kinase inhibitor AG538, PTX and the peptide inhibitor of Gβγ signaling, βARKct. Increases in the activities of Ca(2+) -dependent enzymes calcineurin, calmodulin kinase II (CaMKII), and protein kinase Cα (PKCα) were observed at 5 min after IGF-1 exposure. AG538, PTX, βARKct, and the dominant negative PKCα prevented the IGF-1-dependent phosphorylation of ERK1/2. Participation of calcineurin and CaMKII in ERK phosphorylation was discounted. IGF-1-induced cardiomyocyte hypertrophy, determined by cell size and β-myosin heavy chain (β-MHC), was prevented by AG538, PTX, βARKct, dominant negative PKCα, and the MEK1/2 inhibitor PD98059. Inhibition of calcineurin with CAIN did not abolish IGF-1-induced cardiac hypertrophy. We conclude that IGF-1 induces hypertrophy in cultured cardiomyocytes by activation of the receptor tyrosine kinase activity/βγ-subunits of a PTX-sensitive G protein/Ca(2+) /PKCα/ERK pathway without the participation of calcineurin.
Advanced Center for Chronic Diseases, Universidad de Chile, Santiago, Chile; Centro Estudios Moleculares de la Celula, Facultad de Ciencias y Farmacéuticas, Universidad de Chile, Santiago, Chile.
Loreto
L
Carrasco
Paola
P
Cea
Paola
P
Rocco
Daniel
D
Peña-Oyarzún
Pablo
P
Rivera-Mejias
Cristian
C
Sotomayor-Flores
Clara
C
Quiroga
Alfredo
A
Criollo
Cristian
C
Ibarra
Mario
M
Chiong
Sergio
S
Lavandero
D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D002396:Catechols / Q000494:pharmacology; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D051571:Protein Kinase C-alpha / Q000378:metabolism; D021122:Protein Subunits; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics; D020032:Tyrphostins / Q000494:pharmacology
C419770:AG 538; D002396:Catechols; D010455:Peptides; D021122:Protein Subunits; D011994:Recombinant Proteins; D020032:Tyrphostins; C445259:beta-adrenergic receptor kinase inhibitory peptide; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051571:Protein Kinase C-alpha; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048049:Extracellular Signal-Regulated MAP Kinases; D019703:Calcineurin; D020962:Heterotrimeric GTP-Binding Proteins; D002118:Calcium
CALCIUM; CARDIAC MYOCYTE; EXTRACELLULAR-SIGNAL-REGULATED KINASE; HETEROTRIMERIC G PROTEIN; HYPERTROPHY; INSULIN-LIKE GROWTH FACTOR-1