Inhibition of TLR9-NF-κB-mediated sterile inflammation improves pressure overload-induced right ventricular dysfunction in rats

Keimei Yoshida, Kohtaro Abe, Mariko Ishikawa, Keita Saku, Masako Shinoda-Sakamoto, Tomohito Ishikawa, Takanori Watanabe, Masahiko Oka, Kenji Sunagawa, Hiroyuki Tsutsui

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Aims Recent accumulating evidence suggests that sterile inflammation plays a crucial role in the progression of various cardiovascular diseases. However, its contribution to right ventricular (RV) dysfunction remains unknown. The aim of this study was to elucidate whether toll-like receptor 9 (TLR9)-NF-κB-mediated sterile inflammation plays a critical role in the pathogenesis of RV dysfunction. Methods and results We performed main pulmonary artery banding (PAB) in rats to induce RV pressure overload and dysfunction. On Day 14 after PAB, the pressure overload impaired RV function as indicated by increased RV end-diastolic pressure concomitant with macrophage infiltration and fibrosis, as well as maximal activation of NF-κB and TLR9. Short-term administration (days 14-16 after PAB) of a specific TLR9 inhibitor, E6446, or an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC) significantly attenuated NF-κB activation. Furthermore, long-term administration of E6446 (treatment: days 14-28) or PDTC (prevention: days -1 to 28; treatment: days 14 to 28) improved RV dysfunction associated with mitigated macrophage infiltration and fibrosis in right ventricle and decreased serum brain natriuretic peptide levels. Conclusion Inhibition of TLR9-NF-κB pathway-mediated sterile inflammation improved PAB-induced RV dysfunction in rats. This pathway plays a major role in the progression of pressure overload-induced RV dysfunction and is potentially a novel therapeutic target for the disorder.

Original languageEnglish
Pages (from-to)658-668
Number of pages11
JournalCardiovascular research
Volume115
Issue number3
DOIs
Publication statusPublished - Mar 1 2019

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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