Molecular Therapy: Nucleic Acids (Sep 2021)

Epigenetic Control of circHNRNPH1 in Postischemic Myocardial Fibrosis through Targeting of TGF-β Receptor Type I

  • Weifeng Li,
  • Yue Wang,
  • Yunfei Deng,
  • Huaner Ni,
  • Gu Shen,
  • Xiaoqiang Liu,
  • Jun Li,
  • Fang Wang

Journal volume & issue
Vol. 25
pp. 93 – 104

Abstract

Read online

Postischemic myocardial fibrosis is a factor for the development of cardiac dysfunction and malignant cardiac arrhythmias, and no effective therapy is currently available. Circular RNAs are emerging as important epigenetic players in various biological functions; however, their roles in cardiac fibrosis are unknown. With the use of a rat model of postischemic myocardial fibrosis, we identified an increase in circHNRNPH1 in the ischemic myocardium after myocardial infarction, particularly in cardiac fibroblasts. In cardiac fibroblasts, circHNRNPH1 was responsive to transforming growth factor β1 (TGF-β1), the principal profibrotic factor. The downregulation of circHNRNPH1, in contrast to its overexpression, promoted myofibroblast migration and α-smooth muscle actin and collagen I expression and inhibited myofibroblast apoptosis. The recombinant adeno-associated virus 9 (rAAV9)-mediated, cardiac-specific knockdown of circHNNRPH1 accordingly facilitated cardiac fibrosis and aggravated cardiac dysfunction. Mechanistically, circHNRNPH1 colocalized with and sponged microRNA (miR)-216-5p in the cytoplasm of cardiac fibroblasts to induce SMAD7 (protein family of signal transduction component of the canonical transforming growth factor-β signaling pathway) expression, accelerating the degradation of TGF-β receptor I. Thus, our results indicated that circHNRNPH1 negatively regulates the fibrogenesis of cardiac fibroblasts and may provide a new therapeutic strategy for postischemic myocardial fibrosis.

Keywords