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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:892.)
© 2008 American Heart Association, Inc.

Cell Biology and Signaling

GIT1 Mediates HDAC5 Activation by Angiotensin II in Vascular Smooth Muscle Cells

Jinjiang Pang; Chen Yan; Kanchana Natarajan; Megan E. Cavet; Michael P. Massett; Guoyong Yin; Bradford C. Berk

From the Aab Cardiovascular Research Institute and the Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York.

Correspondence to Bradford C. Berk, MD, PhD, Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 679, Rochester, NY 14642. E-mail Bradford_berk{at}urmc.rochester.edu

Objective— The G protein-coupled receptor (GPCR)-kinase2 interacting protein1 (GIT1) is a scaffold protein involved in angiotensin II (Ang II) signaling. Histone deacetylase-5 (HDAC5) has emerged as an important substrate of calcium/calmodulin-dependent protein kinase II (CamK II) in GPCR signaling. Here we investigated the hypothesis that Ang II-mediated vascular smooth muscle cell (VSMC) gene transcription involves GIT1-CamK II-dependent phosphorylation of HDAC5.

Methods and Results— Ang II rapidly stimulated phosphorylation of HDAC5 at Ser498 in VSMCs. Knockdown of GIT1 significantly decreased HDAC5 phosphorylation induced by Ang II. The involvement of Src, phospholipase (PLC), and CamK II in GIT1-mediated HDAC5 phosphorylation was demonstrated. The association of GIT1 and CamK II was constitutive but increased after stimulation with Ang II. Moreover, the interaction of GIT1 and CamK II through the ARF GTPase-activating protein (ARF-GAP) and coiled-coil domains of GIT1 was essential for the phosphorylation of HDAC5. Finally, knockdown of GIT1 decreased myocyte enhancer factor 2 transcriptional activity induced by Ang II.

Conclusions— This study identifies a novel function for GIT1 as a mediator of Ang II-induced VSMC gene transcription via a Src-PLC-CamK II-HDAC5 signaling pathway.

Key Words: G protein-coupled receptor-kinase interacting protein1 • GIT1 • angiotensin II • histone heacetylase 5 • Ca²⁺-calmodulin-dependent protein kinase II • VSMC