Nuclear receptor subfamily 1 group D member 1 suppresses the proliferation, migration of adventitial fibroblasts, and vascular intimal hyperplasia via mammalian target of rapamycin complex 1/β-catenin pathway

ABSTRACT

Background

In-stent restenosis hardly limits the therapeutic effect of the percutaneous vascular intervention. Although the restenosis is significantly ameliorated after the application of new drug-eluting stents, the incidence of restenosis remains at a high level.

Objective

Vascular adventitial fibroblasts (AFs) play an important role in intimal hyperplasia and subsequent restenosis. The current study was aimed to investigate the role of nuclear receptor subfamily 1, group D, member 1 (NR1D1) in the vascular intimal hyperplasia.

Methods and Results

We observed increased expression of NR1D1 after the transduction of adenovirus carrying Nr1d1 gene (Ad-Nr1d1) in AFs. Ad-Nr1d1 transduction significantly reduced the numbers of total AFs, Ki-67-positive AFs, and the migration rate of AFs. NR1D1 overexpression decreased the expression level of β-catenin and attenuated the phosphorylation of the effectors of mammalian target of rapamycin complex 1 (mTORC1), including mammalian target of rapamycin (mTOR) and 4E binding protein 1 (4EBP1). Restoration of β-catenin by SKL2001 abolished the inhibitory effects of NR1D1 overexpression on the proliferation and migration of AFs. Surprisingly, the restoration of mTORC1 activity by insulin could also reverse the decreased expression of β-catenin, attenuated proliferation, and migration in AFs induced by NR1D1 overexpression. In vivo, we found that SR9009 (an agonist of NR1D1) ameliorated the intimal hyperplasia at days 28 after injury of carotid artery. We further observed that SR9009 attenuated the increased Ki-67-positive AFs, an essential part of vascular restenosis at days 7 after injury to the carotid artery.

Conclusion

These data suggest that NR1D1 inhibits intimal hyperplasia by suppressing the proliferation and migration of AFs in a mTORC1/β-catenin-dependent manner.

KEYWORDS:

• NR1D1
• mTORC1
• β-catenin
• AFs
• neointimal hyperplasia

Author contributions

K.P. and M.L.W. contributed equally to the work. K.P. and M.L.W. conceived the project. D.C.Y. and X.S.S. designed the study. K.P., M.L.W., D.C.Y., X.S.S., and Y.J.Y. supervised the entire research. K.P. and M.L.W. performed most of the experimental work and conducted data analysis. J.W., Q.W., and D.L. provided some technical support. K.P. contributed to the figure preparation. D.C.Y. X.S.S., and Y.J.Y. discussed the study. D.C.Y. and X.S.S. organized the data and wrote the manuscript. All authors reviewed the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/10641963.2023.2178659

Additional information

Funding

This work was supported by the Project of The General Hospital of Western Theater Command (2021-XZYG-A02 to D. Yang, 2021-XZYG-B27 to K. Peng, 2021-XZYG-A01 to Y. Yang, and 2021-XZYG-C41 to X. Sun), the National Natural Science Foundation of China (82100419 to X. Sun and 82070289 to Y. Yang) and Sichuan Science and Technology Program (2022NSFSC0820 to Q. Wang; Incubation Project of The General Hospital of Western Theater Command.