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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2355.)
© 2007 American Heart Association, Inc.

Vascular Biology

Angiotensin II Stimulates Protein Kinase D-Dependent Histone Deacetylase 5 Phosphorylation and Nuclear Export Leading to Vascular Smooth Muscle Cell Hypertrophy

Xiangbin Xu; Chang-Hoon Ha; Chelsea Wong; Weiye Wang; Angelika Hausser; Klaus Pfizenmaier; Eric N. Olson; Timothy A. McKinsey; Zheng-Gen Jin

From the Cardiovascular Research Institute and Department of Medicine (X.X., C.H.H., C.W., Z.G.J.), University of Rochester School of Medicine, NY; Institute of Cell Biology and Immunology (A.H., K.P.), University of Stuttgart, Germany; Myogen (T.A.M.) Inc, Westminster, Colorado; and the Department of Molecular Biology (E.N.O.), University of Texas Southwestern Medical Center at Dallas.

Correspondence to Zheng-Gen Jin, Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 679, Rochester, NY 14642. E-mail zheng-gen_jin{at}urmc.rochester.edu

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.

Methods and 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.

Conclusion— 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.

Angiotensin II is implicated in the pathological vascular remodeling. In this study we demonstrate a critical role of protein kinase D and histone deacetylases 5 in Angiotensin II-induced VSMC hypertrophy, and reveal a new signal pathway for the pathological vascular effects of Angiotensin II.

Key Words: angiotensin • vascular smooth muscle cells • histone deacetylases 5 • protein kinase D • hypertrophy

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