Abstract
Abstract 1146
Pulmonary arterial hypertension (PAH) is often as a result of COPD and contributes to morbidity and mortality of chronic cor pulmonale. Hypoxemia is its main clinical features. The toll-like receptors are a group of type I transmembrane proteins that play a central role in specific recognition of pathagen-associated molecular patterns and are critical for the induction of innate immunity and inflammation. Expression of these innate immune receptors, especially TLR4 in healthy and pathological arteries has implicated its role in the homeostasis of vasculature. Chronic hypoxia-induced PAH is mediated by increased production of reactive oxygen species (ROS). ROS have been linked to activation of toll-like receptor 4 (TLR4) signaling. The present studies investigated the role of TLR4 in the pathogenesis PAH and the underlying mechanisms.
In vitro, pulmonary arterial smooth muscle cells (PASMC) derived from TLR4−/− mice exhibited increased production of intracellular reactive oxygen species (ROS). Furthermore, under hypoxia, the expression of TLR4 in PASMC from WT mice was decreased, ROS production in PASMC from WT mice were increased, suggesting down-regulation of TLR4 may contribute to hypoxia-induced PAH.
Using a hypoxia-induced PAH model, we found that hypoxia induced PAH and increased pulmonary arterial wall thickness in wild type (WT) mice. In contrast, mice deficient in TLR4 spontaneously developed PAH and increased pulmonary arterial wall thickness, which were not further enhanced by hypoxia. Consistent with the development of PAH in TLR4−/− mice, echocardiography confirmed right ventricular hypertrophy and decreased pulmonary arterial acceleration time compared to WT mice. Above results suggest that TLR4 plays an important role in maintaining normal pulmonary vasculature, and that hypoxia induces PAH via TLR4.
In short, these studies demonstrate an important role of TLR4 in maintaining normal pulmonary vasculature and in the development of hypoxia-induced PAH. Genetic ablation of TLR4 and inhibition of TLR4 expression by hypoxia induces PASMC proliferation and vascular remodeling, in association with redox signaling in the pathogenesis of PAH.
Disclosures:
No relevant conflicts of interest to declare.
Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to the development of pulmonary arterial hypertension
