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Beta‐adrenergic receptors regulate cardiomyocyte proliferation via PI3K/AKT pathway and cell cycle kinases in neonatal mouse heart
Author(s) -
XU Yanchun,
Zhang Weizhi,
Yano Naohiro,
Mao Quanfu,
Padbury James,
Tseng YiTang
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.529.5
Subject(s) - pi3k/akt/mtor pathway , protein kinase b , cyclin dependent kinase 1 , kinase , cell growth , endocrinology , blockade , cell cycle , medicine , phosphorylation , biology , signal transduction , microbiology and biotechnology , receptor , chemistry , cell , biochemistry
Objective Chronic β‐adrenergic receptor (βAR) stimulation leads to cardiac hypertrophy. We have demonstrated a cardiac βAR‐PI3K crosstalk in adult mouse. Since both cardiac βAR and PI3K signaling activities are developmentally regulated, with high activities in fetal/early newborn stages, this study was set out to elucidate the biological consequence resulted from the βAR‐PI3K crosstalk in neonatal mouse heart. Methods Newborn (2.5 days old) C57BL/6 mice were treated with propranolol (10 mg/kg, ip) for 1 hr to block βAR. This was followed by treatment with EdU (40 mg/kg, ip) for 4 more hr to monitor cell proliferation. Heart cryosections were processed for double immunofluorescence staining to detect EdU, α‐actinin‐2 and MEF 2A. Cardiac tissue lysates were subject to in vitro lipid kinase assay for measurement of PI3K activity and to Western blotting to measure the expressions of PI3K pathway related proteins and cell cycle machinery proteins. Results βAR blockade significantly decreased cardiomyocyte proliferation (*p<0.05). βAR blockade also significantly reduced cardiac PI3K activity, and phosphorylation of its downstream effectors, including Akt (Ser473 and Thr308), GSK‐3α (Ser21), GSK‐3β (Ser9), FOXO1 (Thr24) and FOXO3a (Thr32, Ser253). However, acute βAR blockade did not affect the levels of mTOR/P70S6K/S6 axis and ERK1/2. βAR blockade also decreased the expression of cell cycle related proteins including p‐Chk1, p‐Chk2 and 14–3‐3 proteins, but increased the expression of Myt‐1 and p‐cdc2. Conclusions Our study suggests a novel mechanism regulating cardiomyocyte proliferation in newborn mouse. This involves the crosstalk from βAR to PI3K signaling pathway and results in alteration in cell cycle.