Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Life Sci. 2021 May 15;273:119239. doi: 10.1016/j.lfs.2021.119239. Epub 2021 Feb 27.
Our previous work revealed the protective effect of Qiliqiangxin (QLQX) on cardiac microvascular endothelial cells (CMECs), but the underlying mechanisms remain unclear. We aimed to investigate whether QLQX exerts its protective effect against high-concentration angiotensin II (Ang II)-induced CMEC apoptosis through the autophagy machinery. CMECs were cultured in high-concentration Ang II (1 μM) medium in the presence or absence of QLQX for 48 h. We found that QLQX obviously inhibited Ang II-triggered autophagosome synthesis and apoptosis in cultured CMECs. QLQX-mediated protection against Ang II-induced CMEC apoptosis was reversed by the autophagy activator rapamycin. Specifically, deletion of ATG7 in cultured CMECs indicated a detrimental role of autophagy in Ang II-induced CMEC apoptosis. QLQX reversed Ang II-mediated ErbB2 phosphorylation impairment. Furthermore, inhibition of ErbB2 phosphorylation with lapatinib in CMECs revealed that QLQX-induced downregulation of Ang II-activated autophagy and apoptosis was ErbB2 phosphorylation-dependent via the AKT-FoxO3a axis. Activation of ErbB2 phosphorylation by Neuregulin-1β achieved a similar CMEC-protective effect as QLQX in high-concentration Ang II medium, and this effect was also abolished by autophagy activation. These results show that the CMEC-protective effect of QLQX under high-concentration Ang II conditions could be partly attributable to QLQX-mediated ErbB2 phosphorylation-dependent downregulation of autophagy via the AKT-FoxO3a axis.
我们之前的工作揭示了芪苈强心（QLQX）对心肌微血管内皮细胞（CMECs）的保护作用，但具体机制尚不清楚。本研究旨在探讨 QLQX 是否通过自噬机制对高浓度血管紧张素 II（Ang II）诱导的 CMEC 凋亡发挥保护作用。将 CMECs 在含有或不含有 QLQX 的高浓度 Ang II（1 μM）培养基中培养 48 h。结果发现，QLQX 明显抑制了 Ang II 诱导的培养 CMECs 中的自噬小体合成和细胞凋亡。自噬激活剂雷帕霉素逆转了 QLQX 介导的对 Ang II 诱导的 CMEC 凋亡的保护作用。具体而言，在培养的 CMECs 中敲除 ATG7 表明自噬在 Ang II 诱导的 CMEC 凋亡中起有害作用。QLQX 逆转了 Ang II 介导的 ErbB2 磷酸化损伤。此外，用 lapatinib 抑制 CMECs 中的 ErbB2 磷酸化表明，QLQX 诱导的下调 Ang II 激活的自噬和凋亡是通过 AKT-FoxO3a 轴依赖于 ErbB2 磷酸化的。Neuregulin-1β 激活 ErbB2 磷酸化在高浓度 Ang II 培养基中产生了与 QLQX 类似的 CMEC 保护作用，而这种作用也被自噬激活所消除。这些结果表明，在高浓度 Ang II 条件下，QLQX 对 CMEC 的保护作用部分归因于 QLQX 介导的 AKT-FoxO3a 轴依赖于 ErbB2 磷酸化的自噬下调。
