Laboratory of Cellular Signaling, Montreal Diabetes Research Center and Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
Am J Physiol Heart Circ Physiol. 2021 Apr 1;320(4):H1543-H1554. doi: 10.1152/ajpheart.00683.2020. Epub 2021 Feb 19.
Angiotensin II (ANG II) regulates an array of physiological and pathological responses in vascular smooth muscle cells (VSMCs) by activating ERK1/2 and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways. We have demonstrated that ANG II and insulin-like growth factor-1 (IGF-1) induce the expression of early growth response protein-1 (Egr-1), a zinc finger transcription factor, which regulates the transcription of cell cycle regulatory genes network in VSMCs. We have reported that IGF-1 induces the phosphorylation of histone deacetylase 5 (HDAC5), which has been implicated in the expression of genes linked to VSMC growth and hypertrophy, via a PI3K/Akt-dependent pathway in VSMCs. However, the involvement of PI3K/Akt pathways in ANG II-induced HDAC5 phosphorylation and the contribution of HDAC5 in Egr-1 expression and hypertrophy in VSMCs remain unexplored. Here, we show that pharmacological blockade of the PI3K/Akt pathway either by wortmannin/SC66 or siRNA-induced silencing of Akt attenuated ANG II-induced HDAC5 phosphorylation and its nuclear export. Moreover, SC66 or Akt knockdown also suppressed ANG II-induced Egr-1 expression. Furthermore, pharmacological inhibition of HDAC5 by MC1568 or TMP-195 or knockdown of HDAC5 and the blockade of the nuclear export of HDAC5 by leptomycin B or KPT-330 significantly reduced ANG II-induced Egr-1 expression. In addition, depletion of either HDAC5 or Egr-1 by siRNA attenuated VSMC hypertrophy in response to ANG II. In summary, our results demonstrate that ANG II-induced HDAC5 phosphorylation and its nuclear exclusion are mediated by PI3K/Akt pathway and HDAC5 is an upstream regulator of Egr-1 expression and hypertrophy in VSMCs. ANG II-induced histone deacetylase 5 (HDAC5) phosphorylation and nuclear export occurs via the phosphoinositide 3-kinase/Akt pathway. Akt, through HDAC5, regulates ANG II-induced expression of early growth response protein-1 (Egr-1), which is a transcription factor linked with vascular dysfunction. Inhibition of HDAC5 exclusion by nuclear export inhibitors suppresses ANG II-induced Egr-1 expression. HDAC5 is an upstream mediator of Egr-1 expression and cell hypertrophy in response to ANG II in vascular smooth muscle cells.
血管平滑肌细胞（VSMCs）中的血管紧张素 II（ANG II）通过激活 ERK1/2 和磷酸肌醇 3-激酶（PI3K）/Akt 信号通路，调节多种生理和病理反应。我们已经证明，ANG II 和胰岛素样生长因子-1（IGF-1）诱导早期生长反应蛋白-1（Egr-1）的表达，Egr-1 是一种锌指转录因子，调节 VSMCs 中细胞周期调节基因网络的转录。我们已经报道，IGF-1 通过 PI3K/Akt 依赖性途径诱导组蛋白去乙酰化酶 5（HDAC5）的磷酸化，该途径与 VSMC 生长和肥大相关的基因表达有关。然而，PI3K/Akt 途径在 ANG II 诱导的 HDAC5 磷酸化中的参与以及 HDAC5 在 VSMCs 中的 Egr-1 表达和肥大中的作用仍未得到探索。在这里，我们表明，通过wortmannin/SC66 或 Akt 特异性 siRNA 诱导的 Akt 沉默抑制 PI3K/Akt 通路的药理学阻断，可减弱 ANG II 诱导的 HDAC5 磷酸化及其核输出。此外，SC66 或 Akt 敲低也抑制了 ANG II 诱导的 Egr-1 表达。此外，通过 MC1568 或 TMP-195 抑制 HDAC5 的药理学作用，或通过莱普霉素 B 或 KPT-330 阻断 HDAC5 的核输出，显著降低了 ANG II 诱导的 Egr-1 表达。此外，通过 siRNA 耗竭 HDAC5 或 Egr-1 可减弱 ANG II 诱导的 VSMC 肥大。总之，我们的结果表明，ANG II 诱导的 HDAC5 磷酸化及其核排除是由 PI3K/Akt 途径介导的，HDAC5 是 VSMCs 中 Egr-1 表达和肥大的上游调节剂。血管紧张素 II（ANG II）诱导的组蛋白去乙酰化酶 5（HDAC5）磷酸化和核输出通过磷酸肌醇 3-激酶/akt 途径发生。Akt 通过 HDAC5 调节 ANG II 诱导的早期生长反应蛋白-1（Egr-1）的表达，Egr-1 是一种与血管功能障碍相关的转录因子。通过核输出抑制剂抑制 HDAC5 排除可抑制 ANG II 诱导的 Egr-1 表达。HDAC5 是血管平滑肌细胞对 ANG II 反应中 Egr-1 表达和细胞肥大的上游介质。
