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 etiology and pathogenesis of the disease. Both vasoconstriction and structural remodeling (enhanced proliferation of VSMC) 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 (NO), 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.

Molecular Mechanisms of Pulmonary Arterial Remodeling

“…Conditions such as shear stress or vascular injury can induce upregulation of cell adhesion molecules (Vascular cell adhesion molecule-1 [VCAM-1], Intracellular adhesion molecule-1 ) that can attract inflammatory mediators (monocytes/macrophages, lymphocytes) to endothelial cells which can contribute to remodeling of the vascular wall (10). Various chemokines (fraktalkine, chemokine ligand 2 [CCL2; also called monocyte chemotactic protein-1 {MCP-1}] and regulated on activation, normal T-cell expressed and secreted [RANTES; also called chemokine ligand 5 {CCL5}]) and receptors (CX3CR1) also are known to be upregulated in the endothelium of PAH patients (11)(12). In fact, the monocrotaline (MCT) rodent model is used widely to study PAH because it triggers severe vascular inflammation, remodeling, and increases pulmonary blood pressure (13).…”

Salvia Miltiorrhiza Bge.f.alba Ameliorates the Progression of Monocrotaline-Induced Pulmonary Hypertension by Protecting Endothelial Injury in Rats

“…This imbalance of vasoactive factors leads to smooth muscle cell proliferation and hyperplasia, which eventually causes vascular remodeling and narrowing of the pulmonary artery lumens (Haworth 2006;Crosswhite and Sun 2010). ET-1 is one of the most potent endogenous vasoconstrictors, and is also a vascular smooth muscle mitogen that participates in the regulation of pulmonary vascular tone and pulmonary vascular remodeling (Tokgöz et al 2010).…”

Pulmonary Hypertension Is a Probable NO/ONOO−Cycle Disease: A Review

“…Oxidative stress and reactive oxygen species were discussed as causal factors in generating the symptoms and signs of PAH in the introduction to this paper [17,22].…”

“…Elevated ONOO − can lead to oxidation of tetrahydrobiopterin (BH4), which may lead, in turn, to what is called the partial uncoupling of the nitric oxide synthases (NOSs), leading in turn to chronic ONOO − elevation and, in some cases, chronic hypertension [14][15][16]. All of these changes, discussed earlier in this paragraph, are thought to be important consequences of the NO/ONOO − cycle and are also thought to be involved in PAH [17,18]. e properties of peroxynitrite (ONOO − ) itself are quite distinct from those of its nitric oxide (NO) precursor, because NO is, of course, a vasodilator.…”