Angiotensin II stimulates protein kinase D-dependent histone deacetylase 5 phosphorylation and nuclear export leading to vascular smooth muscle cell hypertrophy.
BACKGROUND
Angiotensin II (Ang II) induces the phenotypic modulation and hypertrophy of vascular smooth muscle cells (VSMCs), which is implicated in the pathogenesis of hypertension, atherosclerosis, and diabetes. In this study, we tested the hypothesis that histone deacetylases 5 (HDAC5) and its signal pathway play a role in Ang II-induced VSMC hypertrophy.


RESULTS
VSMCs were isolated from the thoracic aortas of male Sprague-Dawley rats and treated with Ang II. We found that Ang II rapidly stimulated phosphorylation of HDAC5 at Serine259/498 residues in a time- and dose- dependent manner. Ang II receptor-1, protein kinase C, and protein kinase D1 (PKD1) mediated HDAC5 phosphorylation. Furthermore, we observed that Ang II stimulated HDAC5 nuclear export, which was dependent on its PKD1-dependent phosphorylation. Consequently, both inhibiting PKD1 and HDAC5 Serine259/498 to Alanine mutant significantly attenuated Ang II-induced myocyte enhancer factor-2 (MEF2) transcriptional activity and protein synthesis in VSMCs.


CONCLUSIONS
These findings demonstrate for the first time that PKD1-dependent HDAC5 phosphorylation and nuclear export mediates Ang II-induced MEF2 activation and VSMC hypertrophy, and suggest that PKD1 and HDAC5 may emerge as potential targets for the treatment of pathological vascular hypertrophy.
Xu
Xiangbin
X
Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine, NY 14642, USA.
Ha
Chang-Hoon
CH
Wong
Chelsea
C
Wang
Weiye
W
Hausser
Angelika
A
Pfizenmaier
Klaus
K
Olson
Eric N
EN
McKinsey
Timothy A
TA
Jin
Zheng-Gen
ZG
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D001013:Aorta, Thoracic / Q000503:physiopathology; D006655:Histone Deacetylases / Q000378:metabolism*; D006984:Hypertrophy; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000473:pathology* / Q000502:physiology*; D011493:Protein Kinase C; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction