IGF-2R-Mediated signaling results in hypertrophy of cultured cardiomyocytes from fetal sheep

Kimberley C Wang, Doug A Brooks, Kimberley J Botting, Janna L Morrison

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

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 6 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 R3IGF-1, an IGF-1R agonist; picropodophyllin, an IGF-1R autophosphorylation inhibitor U0126, an inhibitor of extracellular signal-regulated protein kinase (ERK); Leu27IGF-2, an IGF-2R agonist; Go6976, a protein kinase C inhibitor KN-93, an inhibitor of Ca2+/ 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.

Original languageEnglish
Article number183
Pages (from-to)1-8
Number of pages8
JournalBiology of Reproduction
Volume86
Issue number6
DOIs
Publication statusPublished - 1 Jun 2012
Externally publishedYes

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