title: Unexpected maturation of PI3K and MAPK-ERK signaling in fetal ovine cardiomyocytes.
abstract: In the first two-thirds of gestation, ovine fetal cardiomyocytes undergo mitosis to increase cardiac mass and accommodate fetal growth. Thereafter, some myocytes continue to proliferate while others mature and terminally differentiate into binucleated cells. At term (145 days gestational age; dGA) about 60% of cardiomyocytes become binucleated and exit the cell cycle under hormonal control. Rising thyroid hormone (T3) levels near term (135 dGA) inhibit proliferation and stimulate maturation. However, the degree to which intracellular signaling patterns change with age in response to T3 is unknown. We hypothesized that in vitro activation of ERK, Akt, and p70(S6K) by two regulators of cardiomyocyte cell cycle activity, T3 and insulin like growth factor-1 (IGF-1), would be similar in cardiomyocytes at gestational ages 100 and 135 dGA. IGF-1 and T3 each independently stimulated phosphorylation of ERK, Akt, and p70(S6K) in cells at both ages. In the younger mononucleated myocytes, the phosphorylation of ERK and Akt was reduced in the presence of IGF-1 and T3. However, the same hormone combination led to a dramatic twofold increase in the phosphorylation of these signaling proteins in the 135 dGA cardiomyocytes-even in cells that were not proliferating. In the older cells, both mono- and binucleated cells were affected. In conclusion, fetal ovine cardiomyocytes undergo profound maturation-related changes in signaling in response to T3 and IGF-1, but not to either factor alone. Differences in age-related response are likely to be related to milestones in fetal cardiac development as the myocardium prepares for ex utero life.
authors.affiliation: Center for Developmental Health, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon; chatterg@ohsu.edu.
authors.forename: N N
authors.initials: NN
authors.lastname: Chattergoon
authors.affiliation: Center for Developmental Health, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon; Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon;
authors.forename: S
authors.initials: S
authors.lastname: Louey
authors.affiliation: Center for Developmental Health, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon; Vollum Institute for Advanced Biomedical Research, Oregon Health and Science University, Portland, Oregon; and.
authors.forename: P J
authors.initials: PJ
authors.lastname: Stork
authors.affiliation: Center for Developmental Health, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon; Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon; Portland Veterans Affairs Medical Center, Portland, Oregon.
authors.forename: G D
authors.initials: GD
authors.lastname: Giraud
authors.affiliation: Center for Developmental Health, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon; Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon;
authors.forename: K L
authors.initials: KL
authors.lastname: Thornburg
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005318:Fetal Heart / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D012756:Sheep; D013963:Thyroid Hormones / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D013963:Thyroid Hormones; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: MAPK; PI3K; cardiomyocyte proliferation; fetal heart; thyroid hormone