Abstract 14800: Heterozygous Ablation of RORγt Gene Deteriorates Adverse Cardiac Remodeling After Myocardial Infarction
Background: Inflammatory response is associated with progression of heart failure. Recent studies have revealed that retinoic acid receptor-related orphan nuclear receptor (RORγt) is a critical regulator of T cell functions. Although we have reported that RORγt-expressing (RORγt+) cells participate in pathological process in autoimmune myocarditis, their roles in myocardial infarction (MI) remains to be elucidated.
Methods and results: Murine MI was induced by left coronary artery ligation. The expression of RORγt mRNA expression was increased in infarcted hearts with its peak at 7 days after MI. Immunohistochemical staining revealed that RORγt+ cells infiltrated in the border zone after MI. To clarify the effects of RORγt on cardiac remodeling after MI, the mice with eGFP gene heterozygously knocked-in at RORγt locus (RORγt +/- mice) were generated. RORγt expression was significantly decreased in thymus of RORγt +/- mice, compared with wild-type (WT). MI was generated in RORγt +/- mice and WT mice, as a control. Kaplan-Meier analyses revealed that mortality was increased in RORγt +/- mice compared with WT mice. Masson’s trichrome staining demonstrated that the reduction of RORγt results in exacerbation of cardiac fibrosis at 7 days after MI. Moreover, echocardiography clarified that cardiac function was deteriorated in RORγt +/- mice compared with WT mice (FS: +/-; 32.9±2.9%, WT; 38.3±3.6%, P<0.01). Next, we performed qPCR to measure the mRNA expression of interleukin (IL) -17A, IL-17F and IL-23 receptor, which is regulated by RORγt. The transcripts of these signaling molecules were decreased in infarcted heart of RORγt +/- mice, compared with WT mice. Finally, immunohistochemical analyses revealed that capillary density in border zone was decreased in RORγt +/- mice.
Conclusions: So far, it has been reported that IL-17, which is produced from RORγt+ cells, is detrimental in cardiac remodeling after MI; however, RORγt+ cells ameliorate adverse cardiac remodeling after MI, as a novel function of RORγt+ cells.
Author Disclosures: D. Enomoto: None. M. Obana: None. K. Matsumoto: None. Y. Sakata: None. M. Maeda: None. H. Nakayama: None. Y. Fujio: None.
- © 2016 by American Heart Association, Inc.