TY - JOUR
T1 - GIT1 mediates HDAC5 activation by angiotensin II in vascular smooth muscle cells
AU - Pang, Jinjiang
AU - Yan, Chen
AU - Natarajan, Kanchana
AU - Cavet, Megan E.
AU - Massett, Michael P.
AU - Yin, Guoyong
AU - Berk, Bradford C.
PY - 2008/5
Y1 - 2008/5
N2 - 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 γ (PLCγ), 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-PLCγ-CamK II-HDAC5 signaling pathway.
AB - 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 γ (PLCγ), 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-PLCγ-CamK II-HDAC5 signaling pathway.
KW - Angiotensin II
KW - Ca-calmodulin-dependent protein kinase II
KW - G protein-coupled receptor-kinase interacting protein1
KW - GIT1
KW - Histone heacetylase 5
KW - VSMC
UR - http://www.scopus.com/inward/record.url?scp=42149101188&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.107.161349
DO - 10.1161/ATVBAHA.107.161349
M3 - Article
C2 - 18292392
AN - SCOPUS:42149101188
SN - 1079-5642
VL - 28
SP - 892
EP - 898
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 5
ER -