Interferon regulatory factor 7 protects against vascular smooth muscle cell proliferation and neointima formation.

Abstract

BACKGROUND:

Interferon regulatory factor 7 (IRF7), a member of the interferon regulatory factor family, plays important roles in innate immunity and immune cell differentiation. However, the role of IRF7 in neointima formation is currently unknown.

METHODS AND RESULTS:

Significant decreases in IRF7 expression were observed in vascular smooth muscle cells (VSMCs) following carotid artery injury in vivo and platelet-derived growth factor-BB (PDGF-BB) stimulation in vitro. Compared with non-transgenic (NTG) controls, SMC-specific IRF7 transgenic (IRF7-TG) mice displayed reduced neointima formation and VSMC proliferation in response to carotid injury, whereas a global knockout of IRF7 (IRF7-KO) resulted in the opposite effect. Notably, a novel IRF7-KO rat strain was successfully generated and used to further confirm the effects of IRF7 deletion on the acceleration of intimal hyperplasia based on a balloon injury-induced vascular lesion model. Mechanistically, IRF7's inhibition of carotid thickening and the expression of VSMC proliferation markers was dependent on the interaction of IRF7 with activating transcription factor 3 (ATF3) and its downstream target, proliferating cell nuclear antigen (PCNA). The evidence that IRF7/ATF3-double-TG (DTG) and IRF7/ATF3-double-KO (DKO) mice abolished the regulatory effects exhibited by the IRF7-TG and IRF7-KO mice, respectively, validated the underlying molecular events of IRF7-ATF3 interaction.

CONCLUSIONS:

These findings demonstrated that IRF7 modulated VSMC proliferation and neointima formation by interacting with ATF3, thereby inhibiting the ATF3-mediated induction of PCNA transcription. The results of this study indicate that IRF7 is a novel modulator of neointima formation and VSMC proliferation and may represent a promising target for vascular disease therapy.

• Authors: Ling Huang, Shu-Min Zhang, Peng Zhang, Xiao-Jing Zhang, Li-Hua Zhu, Ke Chen, Lu Gao, Yan Zhang, Xiang-Jie Kong, Song Tian, Xiao-Dong Zhang, Hongliang Li
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 3 Issue 5 Pg. e001309 (Oct 10 2014) ISSN: 2047-9980 [Electronic] England
• PMID: 25304854 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Chemical References

• Activating Transcription Factor 3
• Atf3 protein, rat
• Interferon Regulatory Factor-7

Topics

• Activating Transcription Factor 3 (genetics)
• Animals
• Blotting, Western
• Carotid Artery Injuries (pathology, physiopathology)
• Cell Proliferation (genetics)
• Cells, Cultured
• Disease Models, Animal
• Gene Expression Regulation
• Interferon Regulatory Factor-7 (genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Microscopy, Confocal
• Muscle, Smooth, Vascular (cytology)
• Myocytes, Smooth Muscle (metabolism)
• Neointima (pathology, physiopathology)
• Rats
• Rats, Sprague-Dawley