Abstract 313: Interferon Regulatory Factor 1 Plays an Important Role in Inhibition of Vascular Remodeling Through Angiotensin II Type 2 Receptor
Objective: Transcriptional control of angiotensin II type 2 (AT2) receptor expression is not well known and we previously reported that interferon regulatory factor (IRF)-1 plays physiological roles in “growth”-regulated AT2 receptor expression in fibroblast. We studied whether IRF-1 is involved in the attenuation of vascular remodeling in association with AT2 receptor up-regulation.
Methods: Inflammatory vascular injury was induced by polyethylene-cuff placement around the mouse femoral artery in male wild-type mice (WT: C57BL/6J strain), IRF-1 knockout mice (IRF-1KO) and AT2 receptor-null mice (AT2KO) at 10 weeks of age. After cuff placement, each mice were treated with an intraperitoneal injection of compound 21 (C21), AT2 receptor agonist, at the dose of 10 μg/kg/day or saline. Formalin-fixed, paraffin-embedded sections were prepared using femoral arteries 14 days after cuff placement and subjected to Elastica van Gieson staining for the evaluation of neointima formation. Superoxide anion production and mRNA expressions 7 days after cuff placement were evaluated by dihydroethidium staining and real-time quantitative RT-PCR respectively.
Results: Neointima areas in the injured artery induced by cuff placement were significantly increased in vehicle-treated group of IRF-1KO and AT2KO compared with those in WT. Moreover, we observed that treatment with C21 attenuated neointima formation 76% in WT, but 45% in IRF-1KO. Oxidative stress was more enhanced in vehicle-treated group of IRF-1KO compared with WT. Treatment with C21 markedly inhibited oxidative stress in WT, but not in IRF-1KO. AT2 receptor mRNA expression was significantly decreased in IRF-1KO compared with that in WT; however, IRF-1 mRNA expression did not differ between AT2KO and WT.
Conclusion: These results indicate that IRF-1 up-regulates AT2 receptor expression and thereby plays an important role in the inhibition of vascular remodeling, supporting the notion that IRF-1 is one of the key transcriptional factor for AT2 receptor expression and that targeting the immune system is pivotal in the treatment of vascular diseases.
Author Disclosures: H. Nakaoka: None. M. Mogi: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Modest; JSPS KAKENHI Grant Number 25462220. J. Suzuki: None. H. Kan-no: None. K. Tsukuda: None. T. Chisaka: None. M. Kukida: None. X. Wang: None. H. Bai: None. B. Shan: None. J. Iwanami: None. M. Horiuchi: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Modest; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Daiichi-Sankyo Pharmaceutical Co. Ltd., Nippon Boehringer lngelheim Co. Ltd., Novartis Pharma K. K., Shionogi & Co., Ltd., Takeda Pharmaceutical Co. Ltd, JSPS KAKENHI Grant Number 25293310.
- © 2014 by American Heart Association, Inc.