β2-Adrenergic receptor-induced transactivation of epidermal growth factor receptor and platelet-derived growth factor receptor via Src kinase promotes rat cardiomyocyte survival
β2-Adrenergic receptor-induced transactivation of epidermal growth factor receptor and platelet-derived growth factor receptor via Src kinase promotes rat cardiomyocyte survival
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DOI：
10.1042/cbi20110162
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发表时间：
2012-03-01
影响因子：
3.9
通讯作者：
Xu, Zhiwei
中科院分区：
文献类型：
--
作者：
Chen, Hao;Ma, Ning;Xu, Zhiwei
β-AR（肾上腺素能受体）的慢性刺激会促进心肌细胞凋亡，从而导致心功能障碍。 beta(1)-AR 和 beta 2-AR 是 beta-AR 的主要亚型，对心肌细胞的存活产生不同的影响。为了阐明β(1)-AR和β(2)-AR在心肌细胞中的生理作用，研究了β(1)-AR或β(2)-AR敲低对H9c2心肌细胞存活的影响。 p2-AR（而非β(1)-AR）的敲低抑制了ISO（异丙肾上腺素）诱导的EGFR（表皮生长因子受体）和PDGFR（血小板源性生长因子受体）的磷酸化。 EGFR 抑制剂 AG 1478 可减弱 ERK（细胞外信号调节激酶）激活并部分降低细胞存活率。使用 PDGFR 抑制剂 AG 1296 进行预处理，可消除 ISO 诱导的 Akt（也称为蛋白激酶 B）磷酸化，并导致细胞活力下降。此外，Src 酪氨酸激酶抑制剂 PP2 可阻断 ISO 介导的 Akt 和 ERK 激活，并严重抑制活力。因此，在原代新生大鼠心肌细胞中，β(2)-AR抑制剂而非β(1)-AR抑制剂消除了EGFR和PDGFR的反式激活，这分别与Akt和ERK激活相关。结果表明，β(2)-AR 反式激活 PDGFR 和 EGFR，从而促进心肌细胞的存活。
Chronic stimulation of the beta-AR (adrenergic receptor) promotes apoptosis of cardiomyocytes, which is implicated in cardiac dysfunction. beta(1)-AR and beta 2-AR are the main subtypes of beta-AR that exert distinct effects on the survival of cardiomyocytes. To clarify the physiological roles of beta(1)-AR and beta(2)-AR in cardiomyocytes, the effects of beta(1)-AR or beta(2)-AR knockdown on the survival of H9c2 cardiomyocytes was investigated. Knockdown of p2-AR, but not beta(1)-AR, suppressed the phosphorylation of EGFR (epidermal growth factor receptor) and PDGFR (platelet-derived growth factor receptor) induced by ISO (isoprenaline). The EGFR inhibitor, AG 1478, attenuated ERK (extracellular-signal-regulated kinase) activation and partially decreased cell survival. Pretreatment with AG 1296, a PDGFR inhibitor, abolished ISO-induced Akt (also known as protein kinase B) phosphorylation and led to a decrease in cell viability. In addition, the Src tyrosine kinase inhibitor, PP2, blocked ISO-mediated both Akt and ERK activation and heavily suppressed viability. Accordingly, in primary neonatal rat cardiomyocytes, the beta(2)-AR inhibitor, but not the beta(1)-AR inhibitor, abrogated the transactivation of EGFR and PDGFR, which was respectively related to Akt and ERK activation. The results show that beta(2)-AR transactivates PDGFR and EGFR, thereby promoting survival of cardiomyocytes.