title: Extracellular signal-regulated kinase and phosphoinositol-3 kinase mediate IGF-1 induced proliferation of fetal sheep cardiomyocytes.
abstract: 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 three- to five-fold. The blockade of either ERK or PI3K signaling (by UO-126 or LY-294002, 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; and 4) IGF-1 through IGF1R requires both ERK and PI3K signaling for proliferation of near-term fetal sheep cardiomyocytes in vitro.
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Sundgren
authors.forename: George D
authors.initials: GD
authors.lastname: Giraud
authors.forename: Jess M
authors.initials: JM
authors.lastname: Schultz
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lasarev
authors.forename: Philip J S
authors.initials: PJ
authors.lastname: Stork
authors.forename: Kent L
authors.initials: KL
authors.lastname: Thornburg
mesh_terms: D000818:Animals; D002245:Carbon Dioxide / Q000097:blood; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D005260:Female; D006321:Heart / Q000196:embryology; D006400:Hematocrit; D006863:Hydrogen-Ion Concentration; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D010100:Oxygen / Q000097:blood; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011247:Pregnancy; D012756:Sheep
chemical_list: D002245:Carbon Dioxide; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D010100:Oxygen