Ets-1 is a critical regulator of Ang II-mediated vascular inflammation and remodeling
Yumei Zhan, … , I-Cheng Ho, Peter Oettgen
Yumei Zhan, … , I-Cheng Ho, Peter Oettgen
Published September 1, 2005
Citation Information: J Clin Invest. 2005;115(9):2508-2516. https://doi.org/10.1172/JCI24403.
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Research Article Vascular biology

Ets-1 is a critical regulator of Ang II-mediated vascular inflammation and remodeling

Abstract

Ang II is a central mediator of vascular inflammation and remodeling. The transcription factor Ets-1 is rapidly induced in vascular smooth muscle and endothelial cells of the mouse thoracic aorta in response to systemic Ang II infusion. Arterial wall thickening, perivascular fibrosis, and cardiac hypertrophy are significantly diminished in Ets1–/– mice compared with control mice in response to Ang II. The induction of 2 known targets of Ets-1, cyclin-dependent kinase inhibitor p21CIP and plasminogen activator inhibitor–1 (PAI-1), by Ang II is markedly blunted in the aorta of Ets1–/– mice compared with wild-type controls. Expression of p21CIP in VSMCs leads to cellular hypertrophy, whereas expression of p21CIP in endothelial cells is associated with cell cycle arrest, apoptosis, and endothelial dysfunction. PAI-1 promotes the development of perivascular fibrosis. We have identified monocyte chemoattractant protein–1 (MCP-1) as a novel target for Ets-1. Expression of MCP-1 is similarly reduced in Ets1–/– mice compared with control mice in response to Ang II, which results in significantly diminished recruitment of T cells and macrophages to the vessel wall. In summary, our results support a critical role for Ets-1 as a transcriptional mediator of vascular inflammation and remodeling in response to Ang II.

Authors

Yumei Zhan, Courtney Brown, Elizabeth Maynard, Aleksandra Anshelevich, Weihua Ni, I-Cheng Ho, Peter Oettgen

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Regulation of the human MCP-1 gene by Ets-1. (A) Schematic of the human ...
Regulation of the human MCP-1 gene by Ets-1. (A) Schematic of the human MCP-1 promoter with putative Ets-1 binding sites (filled circles). The transcription start site is indicated by the right arrow, and MCP-1 deletion constructs are designated A, B, and C. Regions used for PCR analysis in the ChIP assay (ChIP1–4) are shown with expected size of PCR fragments. Locations of Ets-1–binding site mutations are shown as M1 (–2,253) and M2 (–402). (B) Transactivation of the MCP-1 promoter (construct A) by a panel of Ets factors in RASMCs shown as fold induction compared with control pCI expression plasmid. (C) ChIP assay of MCP-1 promoter using HASMCs after Ang II stimulation (100 nM) for 2 and 4 hours. An Ets-1 polyclonal antibody was used for precipitation. PCR analysis of the input (control), in the absence of antibody (–Ab), and after immunoprecipitation with antibody (+Ab) using primers corresponding to 4 regions of the MCP-1 promoter. Molecular weight markers are shown on the left. (D) Gel mobility shift assay using oligonucleotide probe encoding the –2,253 MCP-1 promoter Ets-1 site. HASMCs were collected after stimulation with Ang II for 0 (Control), 2, 4, and 16 hours. The 4-hour lysate was incubated with the wild-type oligonucleotide probe, in the presence of either 10 ng of unlabeled (Cold) wild-type or mutant oligonucleotide or 4 μg of an Ets-1 polyclonal antibody or IgG isotype-matched control. (E) Ang II–induced (100 nM) transactivation of deletion constructs A, B, and C and site-directed mutants of the full-length MCP-1 promoter constructs containing the M1, M2, and M1 + M2 mutations in RASMCs are shown as fold induction compared with unstimulated control. (F) Transactivation of deletion constructs A, B, and C and site-directed mutants M1, M2, and M1 + M2 by Ets-1 in RASMCs are shown as fold induction compared with contransfection with empty mammalian expression plasmid.