The orphan nuclear receptor Nur77 inhibits low shear stress-induced carotid artery remodeling in mice

Abstract

Shear stress, particularly low and oscillatory shear stress, plays a critical pathophysiological role in vascular remodeling-related cardiovascular diseases. Growing evidence suggests that the orphan nuclear receptor Nur77 [also known as TR3 or nuclear receptor subfamily 4, group A, member 1 (NR4A1)] is expressed in diseased human vascular tissue and plays an important role in vascular physiology and pathology. In the present study, we used a mouse model of flow-dependent remodeling by partial ligation of the left common carotid artery (LCCA) to define the exact role of Nur77 in vascular remodeling induced by low shear stress. Following vascular remodeling, Nur77 was highly expressed in neointimal vascular smooth muscle cells (VSMCs) in the ligated carotid arteries. The reactive oxygen species (ROS) levels were elevated in the remodeled arteries in vivo and in primary rat VSMCs in vitro following stimulation with platelet-derived growth factor (PDGF). Further in vitro experiments revealed that Nur77 expression was rapidly increased in the VSMCs following stimulation with PDGF and H2O2, whereas treatment with N-acetyl cysteine (NAC, a ROS scavenger) reversed the increase in the protein level of Nur77 induced by H2O2. Moreover, Nur77 overexpression markedly inhibited the proliferation and migration of VSMCs, induced by PDGF. Finally, to determine the in vivo role of Nur77 in low shear stress-induced vascular remodeling, wild-type (WT) and Nur77-deficient mice were subjected to partial ligation of the LCCA. Four weeks following surgery, in the LCCAs of the Nur77-deficient mice, a significant increase in the intima-media area and carotid intima-media thickness was noted, as well as more severe elastin disruption and collagen deposition compared to the WT mice. Immunofluorescence staining revealed an increase in VSMC proliferation [determined by the expression of proliferating cell nuclear antigen (PCNA)] and matrix metalloproteinase 9 (MMP-9) production in the Nur77-deficient mice. There was no difference in the number of intimal apoptotic cells between the groups. Taken together, our results indicate that Nur77 may be a sensor of oxidative stress and an inhibitor of vascular remodeling induced by low shear stress. Nur77, as well as its downstream cell signals, may thus be a potential therapeutic target for the suppression of vascular remodeling.

Targeting nuclear receptor NR4A1–dependent adipocyte progenitor quiescence promotes metabolic adaptation to obesity

“…NR4A1 localized to isolectin-positive blood vessels and to perivascular cells that positively stained for the AP marker PDGFRα. These data suggest high constitutive expression of NR4A1 in APs, but also confirm promiscuous expression in multiple cell types (34)(35)(36)(37)(38)(39). We also investigated whether Nr4a1 expression was dynamically regulated in AT in vivo in physiologically relevant contexts.…”

Single-Cell Analysis of Human Pancreas Reveals Transcriptional Signatures of Aging and Somatic Mutation Patterns

“…Heatmap shows loess fit. Rows marked with a black box indicate genes that are associated with response to stress (Yu et al, 2015; Daugaard et al, 2007; Paneni et al, 2013; Toone et al, 2001). …”

Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues

“…In hepatic stellate cells TGF-β1 was sufficient to drive activation and proliferation. TGF-β1 was observed to increase expression of Nr4a3 and Nr4a3 inhibition impaired primary hepatic stellate cell proliferation, demonstrating Nr4a3′s role in TGF-β1 mediated hepatic stellate cell activation and proliferation [53]. As observed with hepatocytes, the Nr4a subfamily has opposing roles in controlling proliferation which may assist in balancing healthy benign growth.…”