期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 199, 期 2, 页码 199-210出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.201707-1370OC
关键词
pulmonary hypertension; toll-like receptor 3; endothelial cell; double-stranded RNA; apoptosis
资金
- NIHR Clinical Lectureship
- British Heart Foundation-Fulbright Scholarship award
- Fulbright Scholarship award
- British Heart Foundation [FS/13/48/30453, FS/18/13/3328]
- American Heart Association [13SDG16360018]
- NIH/NHLBI [HL114816, HL123044]
- NIH/National Cancer Institute Cancer Center Support Grant [P30 CA016059]
- NHLBI [R24HL123767]
- Cardiovascular Medical Research and Education Fund
- [P01 HL103455]
- British Heart Foundation [FS/13/48/30453] Funding Source: researchfish
Rationale: Pulmonary arterial hypertension (PAH) is characterized by vascular cell proliferation and endothelial cell apoptosis. TLR3 (Toll-like receptor 3) is a receptor for double-stranded RNA and has been recently implicated in vascular protection. Objectives: To study the expression and role of TLR3 in PAH and to determine whether a TLR3 agonist reduces pulmonary hypertension in preclinical models. Methods: Lung tissue and endothelial cells from patients with PAH were investigated by polymerase chain reaction, immunofluorescence, and apoptosis assays. TLR3(-/-) and TLR3(+/+) mice were exposed to chronic hypoxia and SU5416. Chronic hypoxia or chronic hypoxia/SU5416 rats were treated with the TLR3 agonist polyinosinic/polycytidylic acid (Poly[I:C]). Measurements and Main Results: TLR3 expression was reduced in PAH patient lung tissue and endothelial cells, and TLR3(-/-) mice exhibited more severe pulmonary hypertension following exposure to chronic hypoxia/SU5416. TLR3 knockdown promoted double-stranded RNA signaling via other intracellular RNA receptors in endothelial cells. This was associated with greater susceptibility to apoptosis, a known driver of pulmonary vascular remodeling. Poly(I:C) increased TLR3 expression via IL-10 in rat endothelial cells. In vivo, high-dose Poly(I:C) reduced pulmonary hypertension in both rat models in proof-of-principle experiments. In addition, Poly(I:C) also reduced right ventricular failure in established pulmonary hypertension. Conclusions: Our work identifies a novel role for TLR3 in PAH based on the findings that reduced expression of TLR3 contributes to endothelial apoptosis and pulmonary vascular remodeling.
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