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.

The Role of Hyperglycemia and Insulin Resistance in the Development and Progression of Pulmonary Arterial Hypertension.

Pulmonary hypertension is a progressive disorder which often leads to right ventricular failure and death. While the existing classification system for pulmonary hypertension does not account for the impact of diabetes mellitus, evidence is emerging that suggests that diabetes is associated with pulmonary hypertension and that diabetes modifies the course of pulmonary hypertension. There is also growing radiographic, hemodynamic, biochemical, and pathologic data supporting an association between diabetes and pulmonary hypertension. More robust epidemiologic studies are needed to confirm an association between diabetes and pulmonary hypertension and to show that diabetes is a disease modifier in pulmonary hypertension. In addition, evaluating the effects of glucose control in animals with pulmonary hypertension and diabetes (as well as in humans) is warranted.

Development of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.

Pulmonary hypertension (PH) is common in patients with heart failure with preserved ejection fraction (HFpEF). While PH-HFpEF may affect more than a million patients in the United States alone, it has been difficult to study its epidemiology and response to treatment due to difficulty in properly defining the illness. While chronic remodeling of the pulmonary vasculature is related to chronic passive congestion of the pulmonary circulation from the pulmonary veins, there are likely other contributors to the development of PH-HFpEF. We explore the potential direct contributions of obesity, diabetes mellitus, genetics, and sleep apnea on the pulmonary circulation in those with PH-HFpEF, and we discuss the potential role of exercise testing or fluid challenge during diagnostic testing.