Angiotensin II-Induced Histone Deacetylase 5 Phosphorylation, Nuclear Export and Egr-1 Expression is mediated by Akt Pathway in A10 Vascular Smooth Muscle Cells.

Abstract

Angiotensin II (Ang II) regulates an array of physiological and pathological responses in vascular smooth muscle cells (VSMCs) by activating ERK1/2 and PI3K/Akt signaling pathways. We have demonstrated that Ang II and insulin-like growth factor-1 (IGF-1) induces 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 remains 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. Further, 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 is mediated by PI3K/Akt pathway, and HDAC5 is an upstream regulator of Egr-1 expression and hypertrophy in VSMCs.