Temporal and gefitinib-sensitive regulation of cardiac cytokine expression via chronic β-adrenergic receptor stimulation

Chronic stimulation of β-adrenergic receptors (βAR) can promote survival signaling via transactivation of epidermal growth factor receptor (EGFR), but ultimately alters cardiac structure and contractility over time, in part via enhanced cytokine signaling. We hypothesized that chronic catecholamine signaling will have a temporal impact on cardiac transcript expression in vivo, in particular cytokines, and that EGFR transactivation plays a role in this process. C57BL/6 mice underwent infusion with vehicle or isoproterenol (Iso) ± gefitinib (Gef) for 1 or 2 weeks. Cardiac contractility decreased following 2 weeks of Iso treatment, while cardiac hypertrophy, fibrosis and apoptosis were enhanced at both timepoints. Inclusion of Gef preserved contractility, blocked Iso-induced apoptosis and prevented hypertrophy at the 2 week timepoint, but caused fibrosis on its own. RNAseq analysis revealed hundreds of cardiac transcripts altered by Iso at each timepoint with subsequent RT-qPCR validation ...

慢性刺激β肾上腺素能受体(β-adrenergic receptors, βAR)可通过表皮生长因子受体(epidermal growth factor receptor, EGFR)的反式激活促进存活信号通路，但随时间推移最终会改变心脏结构与收缩功能，其部分机制依赖于增强的细胞因子信号通路。本研究假设：慢性儿茶酚胺信号传导会在体内对心脏转录本表达产生时间依赖性影响，尤其是细胞因子的表达，且EGFR反式激活在此过程中发挥作用。将C57BL/6小鼠分别输注溶媒、异丙肾上腺素(isoproterenol, Iso)，或异丙肾上腺素联合吉非替尼(gefitinib, Gef)，处理周期为1周或2周。实验结果显示：经2周异丙肾上腺素处理后，小鼠心脏收缩功能下降；而在两个处理时间点，心脏肥大、纤维化与细胞凋亡水平均有所升高。联合吉非替尼给药可维持心脏收缩功能，阻断异丙肾上腺素诱导的细胞凋亡，并在2周时间点阻止心脏肥大，但吉非替尼单独给药可引发纤维化。RNA测序(RNA-seq)分析显示，在每个时间点均有数百个心脏转录本受异丙肾上腺素调控，后续通过实时定量聚合酶链式反应(real-time quantitative polymerase chain reaction, RT-qPCR)对结果进行了验证……