Reactive oxygen and nitrogen species in pulmonary hypertension

Abstract

Pulmonary vascular disease can be defined as either a disease affecting the pulmonary capillaries and pulmonary arterioles, termed pulmonary arterial hypertension, or a disease affecting the left ventricle, called pulmonary venous hypertension. Pulmonary arterial hypertension (PAH) is a disorder of the pulmonary circulation characterized by endothelial dysfunction, as well as intimal and smooth muscle proliferation. Progressive increases in pulmonary vascular resistance and pressure impair the performance of the right ventricle, resulting in declining cardiac output, reduced exercise capacity, right-heart failure, and ultimately death. While the primary and heritable forms of the disease are thought to affect over 5000 patients in the United States, the disease can occur secondary to congenital heart disease, most advanced lung diseases, and many systemic diseases. Multiple studies implicate oxidative stress in the development of PAH. Further, this oxidative stress has been shown to be associated with alterations in reactive oxygen species (ROS), reactive nitrogen species (RNS), and nitric oxide (NO) signaling pathways, whereby bioavailable NO is decreased and ROS and RNS production are increased. Many canonical ROS and NO signaling pathways are simultaneously disrupted in PAH, with increased expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and xanthine oxidoreductase, uncoupling of endothelial NO synthase (eNOS), and reduction in mitochondrial number, as well as impaired mitochondrial function. Upstream dysregulation of ROS/NO redox homeostasis impairs vascular tone and contributes to the pathological activation of antiapoptotic and mitogenic pathways, leading to cell proliferation and obliteration of the vasculature. This paper will review the available data regarding the role of oxidative and nitrosative stress and endothelial dysfunction in the pathophysiology of pulmonary hypertension, and provide a description of targeted therapies for this disease.

Figure 1

Swan-Ganz Standard Thermodilution Pulmonary Artery Catheter permits measurement of right atrium, right ventricle, pulmonary artery and pulmonary artery wedge pressure (also called pulmonary artery occlusion pressure). To measure the pressure in vivo a balloon is inflated in the tip of this flow-directed catheter. The balloon is inflated to occlude a small distal branch of the pulmonary artery, and then the pressure is measured during occlusion and captures the reflected pressure coming from the left atrium.

Figure 2

The electrical principles found in Ohm’s law are applicable to the pulmonary circulation. Electrically, with a given current flow (I), the voltage (V) that is generated across the resistance is given by I x R. In the case of the pulmonary circulation, for any given blood flow (CO), the blood pressure (BP) that will be generated by this flow through the pulmonary vascular resistance (PVR) is given by the same relation: BP = CO x PVR. BP is defined by the difference between mean pulmonary artery pressure (mPAP) and the pulmonary artery occlusion pressure (PAOP).

Figure 3

The uncoupling of eNOS is a dysfunctional state of the enzyme. In the presence of sufficient L-arginine and BH₄, eNOS produces NO (thick arrow) and limited superoxide (thin arrow). When BH₄ is oxidized to BH₂, uncoupled electrons transferring from the NOS reductase domain to the oxygenase domain are diverted to oxygen (thick arrow) rather than L-arginine (thin arrow).

Figure 4

A schematic representation of the possible interplay of eNOS uncoupling, reactive oxygen species (ROS) and soluble guanylate cyclase (sGC) in the pathogenesis of pulmonary arterial hypertension. Adapted with permission from [245].

Figure 5

Representation of the pathogenesis of hemolysis-associated pulmonary hypertension. Intravascular hemolysis releases red blood cell hemoglobin into plasma, which reacts with NO. Furthermore, hemolysis releases arginase 1, which reduces L-arginine availability to synthesize NO. Xanthine oxidase and NADPH oxidase are upregulated and produce superoxide, which also inhibits NO. Reduced NO bioavailability and bioactivity promotes vasoconstriction, the development of pulmonary hypertension, and activation platelets and the hemostatic system. The pulmonary vascular lesion shown is taken from an autopsy specimen from a 35 year old male patient with sickle cell disease who died of sudden death, and shows severe concentric intimal and smooth muscle hyperplasia characteristic of advanced pulmonary hypertension.

Figure 6

A schematic representation of the process and consequences of nitrite reduction. Nitrite can be metabolized to form NO by various enzymatic and non-enzymatic pathways as oxygen tension and pH decrease. The formation of NO and NO related signaling molecules drives hypoxic signaling and protective effects in a number of disease models. The figure is modified and reproduced with permission from [246].

Figure 7

Schematic showing how changes in the mitochondria cause PAH based on a cancer analogy theory. In this theory, changes in the mitochondria cause a decrease in the production of mitochondria-derived reactive oxygen species, inhibiting redox-sensitive potassium channels in the plasma membrane, causing depolarization, opening of voltage –gated Ca²⁺ channels, influx of Ca²⁺ and constriction.