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ROR?t-expressing cells attenuate cardiac remodeling after myocardial infarction.

ABSTRACT:

Aims

Retinoic acid receptor-related orphan nuclear receptor ?t (ROR?t) is a transcriptional factor responsible for IL-17-producing T-cell differentiation. Although it was demonstrated that ROR?t plays essential roles in the onset of autoimmune myocarditis, pathophysiological significance of ROR?t in cardiac remodeling after myocardial infarction (MI) remains to be fully elucidated.

Methods and results

MI was generated by ligating coronary artery. The expression of ROR?t and IL-17A transcripts increased in murine hearts after MI. Additionally, immunohistochemical staining revealed that ROR?t-expressing cells infiltrated in the border zone after MI. Flow cytometric analysis showed that ROR?t-expressing cells were released from the spleen at day 1 after MI. Though ROR?t-expressing cells in spleen expressed ??TCR or CD4, ??TCR+ cells were major population of ROR?t-expressing cells that infiltrated into post-infarct myocardium. To address the biological functions of ROR?t-expressing cells in infarcted hearts, we used mice with enhanced GFP gene heterozygously knocked-in at ROR?t locus (ROR?t+/- mice), which physiologically showed reduced expression of ROR?t mRNA in thymus. Kaplan-Meier analysis showed that MI-induced mortality was higher in ROR?t+/- mice than wild-type (WT) mice. Masson's trichrome staining demonstrated that cardiac injury was exacerbated in ROR?t+/- mice 7 days after MI (Injured area: ROR?t+/-; 42.1±6.5%, WT; 34.0±3.7%, circumference of injured myocardium: ROR?t+/-; 61.8±4.8%, WT; 49.6±5.1%), accompanied by exacerbation of cardiac function (fractional shortening: ROR?t+/-; 32.9±2.9%, WT; 38.3±3.6%). Moreover, immunohistochemical analyses revealed that capillary density in border zone was significantly reduced in ROR?t+/- mice after MI, compared with WT mice, associated with the reduced expression of angiopoietin 2. Finally, the mRNA expression of ROR?t, IL-17A, IL-17F and IL-23 receptor (IL-23R) mRNA and protein expression of IL-10 were decreased in ROR?t+/- hearts.

Conclusions

Heterozygous deletion of ROR?t gene resulted in aggravated cardiac remodeling, accompanied by reduced capillary density, after MI, suggesting that ROR?t-expressing cells contribute to tissue repair in infarcted myocardium.

SUBMITTER: Enomoto D

PROVIDER: S-EPMC5565178 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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RORγt-expressing cells attenuate cardiac remodeling after myocardial infarction.

Enomoto Daichi D Matsumoto Kotaro K Yamashita Tomomi T Kobayashi Arisa A Maeda Makiko M Nakayama Hiroyuki H Obana Masanori M Fujio Yasushi Y

PloS one 20170821 8

<h4>Aims</h4>Retinoic acid receptor-related orphan nuclear receptor γt (RORγt) is a transcriptional factor responsible for IL-17-producing T-cell differentiation. Although it was demonstrated that RORγt plays essential roles in the onset of autoimmune myocarditis, pathophysiological significance of RORγt in cardiac remodeling after myocardial infarction (MI) remains to be fully elucidated.<h4>Methods and results</h4>MI was generated by ligating coronary artery. The expression of RORγt and IL-17A ...[more]

PMID: 28827845

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