Toll‐like Receptor 3 Is a Therapeutic Target for Pulmonary Hypertension

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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