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1 Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR, USA
2 Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR, USA; Department of Medicine (Cardiology), Oregon Health & Science University, Portland, OR, USA; Portland VA Medical Center, Oregon Health & Science University, Portland, OR, USA
3 Department of Surgery, Oregon Health & Science University, Portland, OR, USA
4 Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, Portland, OR, USA
5 The Vollum Institute, Oregon Health & Science University, Portland, OR, USA; Heart Research Center, Oregon Health & Science University, Portland, OR, USA
6 Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR, USA; Department of Medicine (Cardiology), Oregon Health & Science University, Portland, OR, USA; Heart Research Center, Oregon Health & Science University, Portland, OR, USA
* To whom correspondence should be addressed. E-mail: thornbur{at}ohsu.edu.
Growth of the fetal heart involves cardiomyocyte enlargement, division, and maturation. Insulin like growth factor-1 (IGF-1) is implicated in many aspects of growth and is likely to be important in developmental heart growth. IGF-1 stimulates the IGF-1 receptor (IGF1R) and downstream signaling pathways including extracellular signal-regulated kinase (ERK) and phosphoinositol-3 kinase (PI3K). We hypothesized that IGF-1 stimulates cardiomyocyte proliferation and enlargement through stimulation of the ERK cascade and stimulates cardiomyocyte differentiation through the PI3K cascade. In vivo administration of Long R3 IGF-1 (LR3 IGF-1) did not stimulate cardiomyocyte hypertrophy, but led to a decreased percentage of cells that were binucleated in vivo. In culture, LR3 IGF-1 increased myocyte bromodeoxyuridine (BrdU) uptake by 3-5 fold. The blockade of either ERK or PI3K signaling (by UO126 or LY294002 respectively) completely abolished BrdU uptake stimulated by LR3 IGF-1. LR3 IGF-1 did not increase footprint area, but as expected, phenylephrine stimulated an increase in binucleated cardiomyocyte size. We conclude that 1) IGF-1 through IGF1R stimulates cardiomyocyte division in vivo; hyperplastic growth is the most likely explanation of IGF-1 stimulated heart growth in vivo; 2) IGF-1 through IGF1R does not stimulate binucleation in vitro or in vivo, 3) IGF-1 through IGF1R does not stimulate hypertrophy either in vivo or in vitro, 4) IGF-1 through IGF1R requires both ERK and PI3K signaling for proliferation of near term fetal sheep cardiomyocytes in vitro.
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