Different regulation of p27 and Akt during cardiomyocyte proliferation and hypertrophy

Abstract

Postnatal cardiomyocytes normally grow by hypertrophy but show a limited proliferate response to certain stimuli. Although the proliferative capacity declines shortly after birth, neonatal cardiomyocytes can grow both by hypertrophy and by proliferation. Therefore, we have used neonatal cardiomyocytes to investigate the molecular differences between hypertrophic and proliferative growth of cardiomyocytes. Stimulation of neonatal cardiomyocytes with angiotensin II mainly induced hypertrophy, whereas PDGF only had a minor effect on the size of the myocytes. In contrast, PDGF induced significant proliferation in the cardiomyocyte cultures whereas angiotensin II treatment only resulted in a small increase in the number of cells. Measurement of cyclin D-dependent kinase specific phosphorylation of pRb by immunohistochemistry showed that, both stimuli activate the G1 phase of the cell cycle. By western blotting we found that PDGF-induced proliferation correlates with activation of Akt, inactivation of GSK-3beta and downregulation of the cyclin-dependent kinase inhibitor p27, whereas angiotensin II only had a small effect on Akt, GSK-3beta and p27. Our data support the hypothesis that, the hypertrophic and proliferative responses are both activated by G1 cell cycle molecules. The difference between the two responses appears to be that high amounts of p27 are present during hypertrophic growth, whereas proliferation involves downregulation of p27 and GSK-3beta activity and upregulation of Akt.

Myocardial AKT: The Omnipresent Nexus

“…Consistent with observations of myocardial hyperplasia, in the presence of periostin, nuclear targeted AKT doubles the number of BrdU-positive cardiomyocytes (376). These findings are in agreement with observations of increased AKT activity correlating with proliferation of cardiomyocytes (287, 465), downregulation of AKT upon differentiation (337), and requirement of PI3K-dependent signaling in proliferation (342). Overexpression of NOTCH induces phosphorylation of AKT and proliferative signaling in neonatal and adult cardiomyocytes (75, 110, 245).…”

“…Combined administration of FGF1 and p38 mitogen-activated protein (MAP) kinase inhibitor increases cardiomyocyte mitosis and improves cardiac function after myocardial infarction (177). Platelet-derived growth factor (PDGF)-induced neonatal cardiomyocyte proliferation correlates with AKT activation leading to inactivation of glycogen synthase kinase 3 β (GSK-3 β ) and downregulation of p27 (287). Periostin, a component of the extracellular matrix associated with epithelial-mesenchymal transition during cardiac development, induces cell-cycle reentry of adult cardiomyocytes by activation of AKT but not ERK1/2 (376).…”

Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology

“…Similarly, again in vitro, platelet-derived growth factor (PDGF) increases the proliferation of cardiomyocytes via Akt activation, inactivation of GSK-3beta and the subsequent down-regulation of the cyclin-dependent kinase inhibitor p27 59 . Neuregulin-1 (NRG1), a member of the EGF family, stimulates DNA synthesis in both neonatal and adult cardiomyocytes through its specific receptor ErbB4 60, 61 .…”

SGK1-Sensitive Regulation of Cyclin-Dependent Kinase Inhibitor 1B (p27) in Cardiomyocyte Hypertrophy

“…P27 is strongly expressed in the heart [24] and down-regulated during and suppressing cardiac remodelling following heart failure [28], pressure overload [29], cardiac hypertrophy [24,25,30] and myocardial infarction [31]. P27 expression is up-regulated by genetic knockout of the Nhe1 [32], which participates in the SGK1-sensitive cardiac remodelling following pressure overload [5].…”

“…SGK1 phosphorylation targets include cyclin-dependent kinase inhibitor 1B (p27) [13], a powerful blocker of cell proliferation [24,25]. SGK1 and PKB act downstream of PI3K and phosphorylate p27 T157 and p27 T198 leading to impaired nuclear import of p27 and its accumulation in the cytoplasm [13,26,27].…”