Abstract
Sustained β-adrenergic receptors (βAR) activation leads to cardiac hypertrophy and prevents left ventricular (LV) atrophy during LV unloading. The immediate signaling pathways downstream from βAR stimulation, however, have not been well investigated. The current study was to examine the early cardiac signaling mechanism(s) following βAR stimulation. In adult C57BL/6 mice, acute βAR stimulation induced significant increases in PI3K activity and activation of Akt and ERK1/2 in the heart, but not in lungs or livers. In contrast, the same treatment did not elicit these changes in β1/β2AR double knockout mice. We further showed the specificity of β2AR in this crosstalk as treatment with formoterol, a β2AR-selective agonist, but not dobutamine, a predominantly β1AR agonist, activated cardiac Akt and ERK1/2. Acute βAR stimulation also significantly increased the phosphorylation of mTOR (the mammalian target of rapamycin), P70S6K, ribosomal protein S6, GSK-3α/β (glycogen synthase kinase-3α/β), and FOXO1/3a (the forkhead box family of transcription factors 1 and 3a). Moreover, acute βAR stimulation time-dependently decreased the mRNA levels of the muscle-specific E3 ligases atrogin-1 and muscle ring finger protein-1 (MuRF1) in mouse heart. Our results indicate that acute βAR stimulation in vivo affects multiple cardiac signaling cascades, including the PI3K signaling pathway, ERK1/2, atrogin-1 and MuRF1. These data 1) provide convincing evidence for the crosstalk between βAR and PI3K signaling pathways; 2) confirm the β2AR specificity in this crosstalk in vivo; and 3) identify novel signaling factors involved in cardiac hypertrophy and LV unloading. Understanding of the intricate interplay between β2AR activation and these signaling cascades should provide critical clues to the pathogenesis of cardiac hypertrophy and enable identification of targets for early clinical interaction of cardiac lesions.
Highlights
ISO treatment significantly increased cardiac PI3K activity and phosphorylation of Akt and FOXO1(Thr24) which were not affected by pretreatment with H-89 (Fig. 5).This suggests that the cAMP/PKA signaling pathway is not directly involved with b-adrenergic receptors (bAR) stimulation-mediated activation of PI3K signaling pathway
To investigate whether cardiac atrogin-1 and muscle ring finger protein-1 (MuRF1) are affected by acute bAR stimulation, we examined their mRNA levels by real-time quantitative PCR
Our results provide convincing in vivo evidence for the crosstalk between bAR and PI3K signaling pathway
Summary
We demonstrated that multiple signaling molecules downstream of PI3K are affected following acute bAR stimulation, including Akt, P70S6/mTOR/S6 axis, GSK3a/b and FOXOs. More important, two novel players, atrigin-1 and MuRF1, were shown to be part of the early signaling cascade. Acute bAR stimulation induces increases in PI3K activity and phosphorylation of Akt and ERK1/2 in adult mouse heart Acute ISO treatment increased phosphotyrosine-associated PI3K activity, Akt phosphorylation (Thr308 and Ser473), and ERK1/2 phosphorylation in adult mice (Fig. 1A,B,C).
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