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首页> 外文期刊>Journal of Molecular and Cellular Cardiology >beta-Adrenergic receptor-mediated transactivation of epidermal growth factor receptor decreases cardiomyocyte apoptosis through differential subcellular activation of ERK1/2 and Akt
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beta-Adrenergic receptor-mediated transactivation of epidermal growth factor receptor decreases cardiomyocyte apoptosis through differential subcellular activation of ERK1/2 and Akt

机译：β-肾上腺素能受体介导的表皮生长因子受体反式激活通过差异性亚细胞激活ERK1 / 2和Akt减少心肌细胞凋亡

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摘要

beta-Adrenergic receptor (betaAR)-mediated transactivation of epidermal growth factor receptor (EGFR) has been shown to relay pro-survival effects via unknown mechanisms. We hypothesized that acute betaAR-mediated EGFR transactivation in the heart promotes differential subcellular activation of ERK1/2 and Akt, promoting cell survival through modulation of apoptosis. C57BL/6 mice underwent acute i.p. injection with isoproterenol (ISO) +- AG1478 (EGFR antagonist) to assess the impact of betaAR-mediated EGFR transactivation on the phosphor-ylation of ERK1/2 (P-ERK1/2) and Akt (P-Akt) in distinct cardiac subcellular fractions. Increased P-ERK1/2 and P-Akt were observed in cytosolic, plasma membrane and nuclear fractions following ISO stimulation. Whereas the P-ERK1/2 response was EGFR-sensitive in all fractions, the P-Akt response was EGFR-sensitive only in the plasma membrane and nucleus, results confirmed in primary rat neonatal cardiomyocytes (RNCM). betaAR-mediated EGFR-transactivation also decreased apoptosis in serum-depleted RNCM, as measured via TUNEL as well as caspase 3 activity/cleavage, which were sensitive to the inhibition of either ERK1/2 (PD184352) or Akt (LY-294002) signaling. Caspase 3 activity/cleavage was also sensitive to the inhibition of transcription, which, with an increase in nuclear P-ERK1/2 and P-Akt in response to ISO, suggested that fJAR-mediated EGFR transactivation may regulate apoptotic gene transcription. An Apoptosis PCR Array identified tnfsf10 (TRAIL) to be altered by ISO in an EGFR-sensitive'manner, results confirmed via RT-PCR and ELISA measurement of both membrane-bound and soluble cardiomyocyte TRAIL levels. betaAR-mediated EGFR transactivation induces differential subcellular activation of ERK1/2 and Akt leading to increased cell survival through the modulation of caspase 3 activity and apoptotic gene expression in cardiomyocytes.
机译：已经证明，β-肾上腺素能受体（betaAR）介导的表皮生长因子受体（EGFR）的反式激活可通过未知机制传递生存前效应。我们假设心脏中的急性betaAR介导的EGFR反式激活会促进ERK1 / 2和Akt的亚细胞激活差异，并通过调节细胞凋亡来促进细胞存活。 C57BL / 6小鼠接受了急性腹膜内注射。注射异丙肾上腺素（ISO）+-AG1478（EGFR拮抗剂）以评估betaAR介导的EGFR反式激活对不同心脏亚细胞中ERK1 / 2（P-ERK1 / 2）和Akt（P-Akt）磷酸化的影响分数。 ISO刺激后，在胞质，质膜和核部分中观察到P-ERK1 / 2和P-Akt升高。 P-ERK1 / 2反应在所有部分中均对EGFR敏感，而P-Akt反应仅在质膜和细胞核中对EGFR敏感，这在原代大鼠新生心肌细胞（RNCM）中得到了证实。通过TUNEL和caspase 3活性/裂解检测，betaAR介导的EGFR反式激活还减少了血清贫血RNCM中的凋亡，这对ERK1 / 2（PD184352）或Akt（LY-294002）信号转导的抑制都很敏感。 。 Caspase 3活性/裂解对转录的抑制也很敏感，随着对ISO的响应，核P-ERK1 / 2和P-Akt的增加，表明fJAR介导的EGFR反式激活可能调节凋亡基因的转录。细胞凋亡PCR阵列鉴定出tnfsf10（TRAIL）在EGFR敏感状态下被ISO改变，结果通过RT-PCR和ELISA测定了膜结合和可溶性心肌细胞TRAIL的水平。 betaAR介导的EGFR反式激活可诱导ERK1 / 2和Akt的亚细胞差异激活，从而通过调节caspase 3活性和心肌细胞凋亡基因的表达来提高细胞存活率。

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