title: IGF-2R-mediated signaling results in hypertrophy of cultured cardiomyocytes from fetal sheep.
abstract: Activation of the insulin-like growth factor-1 receptor (IGF-1R) is known to play a role in cardiomyocyte hypertrophy. While IGF-2R is understood to be a clearance receptor for IGF-2, there is also evidence that it may play a role in the induction of pathological cardiomyocyte hypertrophy. It is not known whether IGF-2R activates cardiomyocyte hypertrophy during growth of the fetal heart. Fetal sheep hearts (125 ± 0.4 days gestation) were dissected, and the cardiomyocytes isolated from the left and right ventricles for culturing. Cultured cardiomyocytes were treated with either LONG R(3)IGF-1, an IGF-1R agonist; picropodophyllin, an IGF-1R autophosphorylation inhibitor; U0126, an inhibitor of extracellular signal-regulated protein kinase (ERK); Leu(27)IGF-2, an IGF-2R agonist; Gö6976, a protein kinase C inhibitor; KN-93, an inhibitor of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII); or KN-92, an L-type calcium channel inhibitor and negative control for KN-93. The cross-sectional area of cultured cardiomyocytes was determined relative to control cardiomyocytes treated with serum-free culture medium. IGF-1R and IGF-2R activation each resulted in ERK signaling, but IGF-2R activation alone induced CaMKII signaling, resulting in hypertrophy of cardiomyocytes in the late gestation sheep fetus. These data suggest that changes in the intrauterine environment that result in increased cardiac IGF-2R may also lead to cardiomyocyte hypertrophy in the fetus and potentially an increased risk of cardiovascular disease in adult life.
authors.affiliation: Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Kimberley C W
authors.initials: KC
authors.lastname: Wang
authors.forename: Doug A
authors.initials: DA
authors.lastname: Brooks
authors.forename: Kimberley J
authors.initials: KJ
authors.lastname: Botting
authors.forename: Janna L
authors.initials: JL
authors.lastname: Morrison
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005315:Fetal Diseases / Q000209:etiology* / Q000378:metabolism; D006984:Hypertrophy; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D012756:Sheep
chemical_list: D017527:Receptor, IGF Type 2; D017526:Receptor, IGF Type 1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2