Abstract 12813: Orphan Nuclear Receptor Nur77 Inhibits Angiotensin Ii-induced Vascular Remodeling via Downregulation of β-catenin Activity
Background: Angiotensin II (Ang II) is the predominant effector peptide of the renin-angiotensin system (RAS). Ang II contributes to vascular remodeling in many cardiovascular diseases (e.g., hypertension, atherosclerosis, restenosis, and aneurysm). Orphan nuclear receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II-induced vascular remodeling.
Methods and Results: Male Nur77-/- and wildtype (WT) littermate control mice (12-16 weeks of age) were continuously infused with Ang II using a mini-osmotic pump. Nur77 expression was increased in medial vascular smooth muscle cells (VSMCs) of thoracic aorta from WT mice after 2 weeks of exogenous Ang II administration. Loss of Nur77 resulted in enhanced outward vascular remodeling as reflected by increased medial area (197000±7091 μm2 vs. 174000±5927 μm2, p<0.05) and luminal diameter (880.7±24.13 μm vs. 825.2±10.38 μm, p<0.05), and more severe elastin disruption and collagen deposition. In situ immunofluorescence analysis indicated that there were increases in VSMC proliferation and matrix metalloproteinases (MMPs) production, and decreases in the expression of VSMC-specific contractile genes, accompanied by elevated β-catenin expression in remodeling aortas from Nur77-/- mice compared with WT mice. We also isolated rat VSMCs from Sprague-Dawley rats and mouse VSMCs from WT and Nur77-/- mice, and stimulated them with Ang II in vitro. Ang II increased Nur77 expression via the MAPK/PKA-CREB signaling pathway in rat VSMCs. Under both basal and Ang II-induced conditions, Nur77-/-mouse VSMCs exhibited increased proliferation and migration, and reduced expression of VSMC-specific genes. The results of additional experiments suggested that Nur77 suppressed Ang II-induced β-catenin signaling pathway activation by promoting β-catenin degradation and inhibiting its transcriptional activity.
Conclusions: These results indicated that Nur77 is a critical negative regulator of Ang II-induced VSMC proliferation, migration, and phenotypic switching via the downregulation of β-catenin activity. Nur77 may reduce the Ang II-induced vascular remodeling that occurs in many cardiovascular diseases.
Author Disclosures: M. Cui: None. Z. Cai: None. S. Chu: None. Y. Yu: None. Z. Sun: None. P. Nie: None. S. Sun: None. X. Wang: None. L. Hu: None. J. Yi: None. L. Shen: None. B. He: None.
- © 2015 by American Heart Association, Inc.