Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II-Induced Vascular Remodeling via Downregulation of β-Catenin.

Abstract

Angiotensin II (Ang II) is the predominant effector peptide of the renin-angiotensin system. Ang II contributes to vascular remodeling in many cardiovascular diseases (eg, 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. Nur77 expression was initially found to be elevated in medial vascular smooth muscle cells (VSMCs) of thoracic aortas from mice continuously infused with Ang II for 2 weeks using a subcutaneous osmotic minipump. Cellular studies revealed that Nur77 expression was upregulated by Ang II via the MAPK/PKA-CREB signaling pathway. Ang II-induced proliferation, migration, and phenotypic switching were significantly enhanced in VSMCs isolated from Nur77(-/-) mice compared with wild-type VSMCs. Consistent with the role in VSMCs, we found that compared with wild-type mice, Nur77(-/-) mice had elevated aortic medial areas and luminal diameters, more severe elastin disruption and collagen deposition, increased VSMC proliferation and matrix metalloproteinase production, and decreased VSMC-specific genes SM-22α and α-actin expression, after 2 weeks of exogenous Ang II administration. 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. Our findings 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 Ang II-induced vascular remodeling involved in many cardiovascular diseases.

• Authors: Mingli Cui, Zhaohua Cai, Shichun Chu, Zhe Sun, Xiaolei Wang, Liuhua Hu, Jing Yi, Linghong Shen, Ben He
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 67 Issue 1 Pg. 153-62 (Jan 2016) ISSN: 1524-4563 [Electronic] United States
• PMID: 26597820 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• Nuclear Receptor Subfamily 4, Group A, Member 1
• beta Catenin
• Angiotensin II
• DNA

Topics

• Angiotensin II (toxicity)
• Animals
• Cardiovascular Diseases (genetics, physiopathology)
• DNA (genetics)
• Disease Models, Animal
• Down-Regulation
• Gene Expression Regulation
• Male
• Mice
• Mice, Inbred C57BL
• Nuclear Receptor Subfamily 4, Group A, Member 1 (biosynthesis, genetics)
• Vascular Remodeling (physiology)
• beta Catenin (metabolism)