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.

Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway

“…Stimulation by IGF-1 could be blocked by PI 3-kinase inhibition using the LY294002 compound [39]. However, the maximum amount of stimulation achievable was only about 5% of the cells, which is much lower than the levels observed in the current study with human ES-derived cardiomyocytes.…”

Thyroid hormone inhibits proliferation of fetal cardiac myocytes in vitro

“…From our studies, we know that fetal heart weight and BrdU uptake increase in response to elevated IGF-I levels indicating that the proliferation of myocytes in the late-term fetus continues to be important in building heart cell numbers (Sundgren et al 2003a). In another study, subpressor levels of cortisol infused into the circumflex coronary artery resulted in an increased HW:BW ratio without affecting LV or RV myocyte size or maturational state.…”

“…It is clear that the last third of ovine gestation is a critical window for the developing myocardium because during that period the heart must gain the complement of cardiomyocytes that will carry it through the stress-laden birth transition. During this period, both mono-and bi-nucleated myocyte populations are sensitive to nutritional, hormonal, and hemodynamic modifications (Barbera et al 2000, Sundgren et al 2003a, Giraud et al 2006.…”

Signaling mechanisms leading to regulation of proliferation and differentiation of the mesenchymal chondrogenic cell line RCJ3.1C5.18 in response to IGF-I

“…In this context, it should be noted that the activation of different signaling pathways involved in IGF-I-mediated cell proliferation is clearly cell-type specific. For example, the proliferation of fetal brown adipocytes in response to IGF-I is mediated through activation of the MAPK/ERK1/2 pathway (Porras et al 1998), whereas parallel PI-3 kinase and MAPK/ERK1/2 pathways subserve the mitogenic action of IGF-I in cardiomyocytes (Sundgren et al 2003). Interestingly, in the skeletal myoblast cell line L6A1 only the MAPK/ERK1/2 pathway, not the PI-3 kinase pathway, is responsible for the mitogenic response of IGF-I (Samuel et al 1999).…”