Angiotensin II Stimulates Histone Deacetylase 5 Phosphorylation and Nuclear Export via AT1‐PKC‐PKD Pathway Leading to Vascular Smooth Muscle Cell Hypertrophy

Angiotensin II (Ang II) induces the phenotypic modulation and hypertrophy of vascular smooth muscle cells (VSMCs), which is implicated in the pathogenesis of hypertension and atherosclerosis. Here we established a novel role of histone deacetylases 5 (HDAC5) in Ang II‐induced VSMC hypertrophy. We showed that Ang II rapidly stimulated phosphorylation of HDAC5 (p‐HDAC5) on Ser259/498 sites in a time‐ and dose‐ dependent manner in rat aortic VSMCs. Ang II receptor 1 mediated p‐HDAC5. Protein kinase C (PKC) inhibitors, GF109203X and Gö6983, inhibited p‐HDAC5. Using pharmacological inhibitor, siRNA and adenovirus encoding kinase‐negative mutant of protein kinase D (PKD) demonstrated that PKD was essential for p‐HDAC5 by Ang II. Moreover, we showed that Ang II stimulated HDAC5 nuclear export, which was dependent on its phosphorylation via PKC/PKD pathway, because HDAC5 nuclear export was abolished by inhibiting PKC and PKD and by infection of adenovirus encoding HDAC5 S259/498A mutant. Furthermore, both PKD inhibition and HDAC5 S259/498A mutant blocked Ang II‐induced myocyte enhancer factor 2 (MEF2) transcriptional activation. Importantly, Ang II promoted VSMC protein synthesis in PKD and HDAC5‐dependent manner. Our findings reveal for the first time that PKD and HDAC5 play a key role in Ang II‐induced VSMC hypertrophy, and suggest that PKD and HDAC5 may emerge as potential targets for cardiovascular diseases.