The Counter-Regulatory Effects of ESE-1 During Angiotensin II-Mediated Vascular Inflammation and Remodeling

E26 transformation-specific sequence (ETS) factors are a family of transcription factors that share a highly conserved DNA-binding domain. The name ETS originates from a sequence that was detected in an avian erythroblastosis virus, E26, where it formed a transforming gene together with Δgag and c-myb.1,2 There are ~25–30 ETS family members in a variety of species from drosophila to man. ETS factors are involved in regulating a wide variety of biological processes including normal development and differentiation.3 As proto-oncogenes they have also been implicated in the pathogenesis of several different types of cancer.4,5 The epithelium-specific ETS transcription factor-1 (ESE-1) was originally identified as an epithelial-restricted ETS factor.6 Under noninflammatory conditions, ESE-1 is only expressed in cells of epithelial origin. However, in response to inflammatory stimuli such as endotoxin or proinflammatory cytokines including interleukin-1β (IL-1β) or tumor necrosis factor-α (TNF-α), this transcription factor is highly induced in cultured primary endothelial cells or vascular smooth muscle cells (VSMCs).7 In a mouse model of endotoxemia, ESE-1 is rapidly induced in the endothelium and first medial layer of VSMC of the mouse aorta.7 Target genes regulated by ESE-1 include nitric oxide synthase 2 (NOS2) and cyclooxygenase 2 (COX2).7,8 ESE-1 has also recently been shown to function in the regulation of TNF-α-mediated expression of angiopoietin-1 in the setting of inflammatory arthritis.9 The transcriptional activity of ESE-1 can be positively and negatively modified by its interaction with other proteins. Whereas binding of ESE-1 to CBP and p300 is associated with an increase in the transcriptional activity of ESE-1, interaction with Ku proteins represses ESE-1 function.10 ETS factors have also been shown to play an important role in angiotensin II (Ang II)–mediated vascular inflammation and remodeling. In particular, we have previously shown that the prototypic member of the ETS family, Ets-1, is a critical transcriptional mediator of Ang II–mediated vascular inflammatory responses.11 The participation of other selected ETS factors in vascular inflammation was recently reviewed.12 However, the role of ESE-1 in Ang II–mediated vascular inflammation and remodeling has not previously been explored. The primary purpose of this study was to determine whether ESE-1 expression is similarly induced in vivo, in the vasculature, in response to Ang II stimulation, and secondarily to determine whether or not ESE-1 plays an important modulatory role by positively or negatively regulating vascular inflammatory responses to Ang II.