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(Circulation Research. 2008;102:51.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Nitric Oxide Modulates Chromatin Folding in Human Endothelial Cells via Protein Phosphatase 2A Activation and Class II Histone Deacetylases Nuclear Shuttling

Barbara Illi^*, Claudio Dello Russo^*, Claudia Colussi, Jessica Rosati, Michele Pallaoro, Francesco Spallotta, Dante Rotili, Sergio Valente, Gianluca Ragone, Fabio Martelli, Paolo Biglioli, Christian Steinkuhler, Paola Gallinari, Antonello Mai, Maurizio C. Capogrossi, Carlo Gaetano

From the Laboratorio di Biologia Vascolare e Terapia Genica (B.I., F.S.), Centro Cardiologico Fondazione "I. Monzino", IRCCS, Milan; Istituto di Ricerche di Biologia Molecolare I.R.B.M. P. Angeletti (C.D.R., C.S., P.G.), Via Pontina km 30 600, Pomezia, Rome; Laboratorio di Patologia Vascolare (C.C., J.R., G.R., F.M., M.C.C.), Istituto Dermopatico dell’ Immacolata-IRCCS, Rome; Università di Siena (M.P.), Siena; Dipartimento di Cardiochirurgia (P.B.), Centro Cardiologico Fondazione "I. Monzino", IRCCS, Milan; Istituto Pasteur-Fondazione Cenci Bolognetti (D.R., S.V., A.M.), Dipartimento Studi Farmaceutici Università degli Studi di Roma "La Sapienza", Rome, Italy.

Correspondence to Barbara Illi, PhD, Centro Cardiologico Fondazione "I. Monzino", Milan, Italy. E-mail b.illi{at}idi.it

Nitric oxide (NO) modulates important endothelial cell (EC) functions and gene expression by a molecular mechanism which is still poorly characterized. Here we show that in human umbilical vein ECs (HUVECs) NO inhibited serum-induced histone acetylation and enhanced histone deacetylase (HDAC) activity. By immunofluorescence and Western blot analyses it was found that NO induced class II HDAC4 and 5 nuclear shuttling and that class II HDACs selective inhibitor MC1568 rescued serum-dependent histone acetylation above control level in NO-treated HUVECs. In contrast, class I HDACs inhibitor MS27–275 had no effect, indicating a specific role for class II HDACs in NO-dependent histone deacetylation. In addition, it was found that NO ability to induce HDAC4 and HDAC5 nuclear shuttling involved the activation of the protein phosphatase 2A (PP2A). In fact, HDAC4 nuclear translocation was impaired in ECs expressing small-t antigen and exposed to NO. Finally, in cells engineered to express a HDAC4-Flag fusion protein, NO induced the formation of a macromolecular complex including HDAC4, HDAC3, HDAC5, and an active PP2A. The present results show that NO-dependent PP2A activation plays a key role in class II HDACs nuclear translocation.

Key Words: nitric oxide • endothelial cells • histone deacetylases • chromatin

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