Role of heterotrimeric G protein and calcium in cardiomyocyte hypertrophy induced by IGF-1

Abstract

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 Ca2þ levels through a pertussis toxin (PTX)‐sensitive G protein. Here we investigate whether this Ca2þ signal is involved in IGF‐1‐induced cardiomyocyte hypertrophy. Our results show that the IGF‐1‐induced increase in Ca2þ level is abolished by the IGF‐1 receptor tyrosine kinase inhibitor AG538, PTX and the peptide inhibitor of Gbg signaling, bARKct. Increases in the activities of Ca2þ‐dependent enzymes calcineurin, calmodulin kinase II (CaMKII), and protein kinase Ca (PKCa) were observed at 5 min after IGF‐1 exposure. AG538, PTX, bARKct, and the dominant negative PKCa 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 b‐myosin heavy chain (b‐MHC), was prevented by AG538, PTX, bARKct, dominant negative PKCa, 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/bg‐subunits of a PTX‐sensitive G protein/Ca2þ/PKCa/ERK pathway without the participation of calcineurin.