TY - JOUR
T1 - Chronic inhibition of toll-like receptor 9 ameliorates pulmonary hypertension in rats
AU - Ishikawa, Tomohito
AU - Abe, Kohtaro
AU - Takana-Ishikawa, Mariko
AU - Yoshida, Keimei
AU - Watanabe, Takanori
AU - Imakiire, Satomi
AU - Hosokawa, Kazuya
AU - Hirano, Mayumi
AU - Hirano, Katsuya
AU - Tsutsui, Hiroyuki
N1 - Funding Information:
Abe worked in a department endowed by Actelion Pharmaceuticals Japan, and received a research grant from Mochida Pharmaceutical Co. H. Tsutsui received honoraria from Daiichi Sankyo, Inc., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Boehringer Ingelheim Japan, Inc., Novartis Pharma K.K., Bayer Yakuhin, Ltd., Bristol-Myers Squibb KK, and Astellas Pharma Inc., and research funds from Actelion Pharmaceuticals Japan, Daiichi Sankyo, Inc., and Astellas Pharma Inc. The remaining authors have no disclosures to report.
Funding Information:
This work was supported by supported by JSPS KAKENHI Grant (17K09591 and 20K08425) and Japan Agency for Medical Research and Development (18ek0109371h0001).
Publisher Copyright:
© 2021 The Authors.
PY - 2021
Y1 - 2021
N2 - BACKGROUND: Recent accumulating evidence suggests that toll-like receptor 9 (TLR9) is involved in the pathogenesis of cardiovascular diseases. However, its role in pulmonary hypertension remains uncertain. We hypothesized that TLR9 is involved in the development of pulmonary hypertension. METHODS AND RESULTS: A rat model of monocrotaline-induced pulmonary hypertension was used to investigate the effects of TLR9 on hemodynamic parameters, vascular remodeling, and survival. Monocrotaline-exposed rats significantly showed increases in plasma levels of mitochondrial DNA markers, which are recognized by TLR9, TLR9 activation in the lung, and interleukin-6 mRNA level in the lung on day 14 after monocrotaline injection. Meanwhile, monocrotaline-exposed rats showed elevated right ventricular systolic pressure, total pulmonary vascular resistance index and vascular remodeling, together with macrophage accumulation on day 21. In the preventive protocol, administration (days −3 to 21 after monocrotaline injection) of selective (E6446) or nonselective TLR9 inhibitor (chloroquine) significantly ameliorated the elevations of right ventricular systolic pressure and total pulmonary vascular resistance index as well as vascular remodeling and macrophage accumulation on day 21. These inhibitors also significantly reduced NF-κB activation and interleukin-6 mRNA levels to a similar extent. In the short-term reversal protocol, E646 treatment (days 14–17 after monocrotaline injection) almost normalized NF-κB activation and interleukin-6 mRNA level, and reduced macrophage accumulation. In the prolonged reversal protocol, E6446 treatment (days 14–24 after monocrotaline injection) reversed total pulmonary vascular resistance index and vascular remodeling, and improved survival in monocrotaline-exposed rats. CONCLUSIONS: TLR9 is involved in the development of pulmonary hypertension concomitant via activation of the NF-κB‒IL-6 pathway. Inhibition of TLR9 may be a novel therapeutic strategy for pulmonary hypertension.
AB - BACKGROUND: Recent accumulating evidence suggests that toll-like receptor 9 (TLR9) is involved in the pathogenesis of cardiovascular diseases. However, its role in pulmonary hypertension remains uncertain. We hypothesized that TLR9 is involved in the development of pulmonary hypertension. METHODS AND RESULTS: A rat model of monocrotaline-induced pulmonary hypertension was used to investigate the effects of TLR9 on hemodynamic parameters, vascular remodeling, and survival. Monocrotaline-exposed rats significantly showed increases in plasma levels of mitochondrial DNA markers, which are recognized by TLR9, TLR9 activation in the lung, and interleukin-6 mRNA level in the lung on day 14 after monocrotaline injection. Meanwhile, monocrotaline-exposed rats showed elevated right ventricular systolic pressure, total pulmonary vascular resistance index and vascular remodeling, together with macrophage accumulation on day 21. In the preventive protocol, administration (days −3 to 21 after monocrotaline injection) of selective (E6446) or nonselective TLR9 inhibitor (chloroquine) significantly ameliorated the elevations of right ventricular systolic pressure and total pulmonary vascular resistance index as well as vascular remodeling and macrophage accumulation on day 21. These inhibitors also significantly reduced NF-κB activation and interleukin-6 mRNA levels to a similar extent. In the short-term reversal protocol, E646 treatment (days 14–17 after monocrotaline injection) almost normalized NF-κB activation and interleukin-6 mRNA level, and reduced macrophage accumulation. In the prolonged reversal protocol, E6446 treatment (days 14–24 after monocrotaline injection) reversed total pulmonary vascular resistance index and vascular remodeling, and improved survival in monocrotaline-exposed rats. CONCLUSIONS: TLR9 is involved in the development of pulmonary hypertension concomitant via activation of the NF-κB‒IL-6 pathway. Inhibition of TLR9 may be a novel therapeutic strategy for pulmonary hypertension.
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U2 - 10.1161/JAHA.120.019247
DO - 10.1161/JAHA.120.019247
M3 - Article
C2 - 33787285
AN - SCOPUS:85104047957
VL - 10
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
SN - 2047-9980
IS - 7
M1 - e019247
ER -