Nitric oxide, oxidative stress and inflammation in pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a chronic and progressive disease characterized by a persistent elevation of pulmonary artery pressure accompanied by right ventricular hypertrophy (RVH). The current treatment for pulmonary hypertension is limited and only provides symptomatic relief due to unknown cause and pathogenesis of the disease. Both vasoconstriction and structural remodeling (enhanced proliferation of vascular smooth muscle cell) of the pulmonary arteries contribute to the progressive course of PAH, irrespective of different underlying causes. The exact molecular mechanism of PAH, however, is not fully understood. The purpose of this review is to provide recent advances in the mechanistic investigation of PAH. Specifically, this review focuses on nitric oxide, oxidative stress and inflammation and how these factors contribute to the development and progression of PAH. This review also discusses recent and potential therapeutic advancements for the treatment of PAH.

Figure 1

Nitric Oxide, Oxidative Stress and Inflammation in Pulmonary Hypertension. Despite advancements in PAH research in the last 20 years, the initiating factors in most patients remains unclear. Whatever the initiating insult, endothelial cell activation occurs leading to an increase in expression of cell adhesion molecules and production of chemokines and cytokines. Infiltration of inflammatory mediators (lymphocytes, monocytes and macrophages) occurs as well as production of growth factors. Disturbance of the endothelial cells also results in the alteration of nitric oxide signaling leading to a decrease in eNOS expression and NO production. Shear stress on vascular wall and inflammatory infiltrates can lead to the activation of oxidative stress mechanisms such as superoxide generating NADPH oxidases, mitochondrial reactive oxygen species (ROS) production, decreases in hydrogen sulfide (H2S) levels and increases in serotonin (5-HT) levels. These mechanisms act cumulatively causing a decrease in vasodilators (NO, prostacyclins) and a increase in vasoconstrictors (ET-1, thromboxanes). This imbalance of vasoactive substance leads to endothelial cell dysfunction and smooth muscle cell proliferation and hyperplasia eventually causing vascular remodeling and narrowing of the pulmonary arteries. Occlusion of the pulmonary arteries increases pulmonary vascular resistance (PVR) and pulmonary artery blood pressure (PABP) leading to pulmonary arterial hypertension.