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 as 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 5,000 patients in the U.S., 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 anti-apoptotic and mitogenic pathways, leading to cell proliferation and obliteration of the vasculature. This manuscript 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.

Effects of ovariectomy on antioxidant defence systems in the right ventricle of female rats with pulmonary arterial hypertension induced by monocrotaline

“…The elevation in ROS levels was associated with reduced NOS activity, suggesting lower NO bioavailability. This decrease in NO bioavailability could also be attributed to the interaction of caveolin-1 with eNOS, an effect which has previously been associated with PAH development (Tabima et al 2012). However, a compensatory response of the classical antioxidant defence system, SOD, CAT and GPx, was noticed.…”

“…Oxidative stress is involved in PAH (Takano et al 2003), since ROS can modulate vascular tone, smooth muscle cell proliferation, vascular remodelling, and apoptosis. ROS levels are directly associated with the progression from RV hypertrophy to heart failure (Tabima et al 2012). However, there are some aspects about the influence of estrogen on RV oxidative stress in female rats with PAH that have not yet been explored.…”

Rhodiola: An Ordinary Plant or a Promising Future Therapy for Pulmonary Hypertension? A Brief Review

“…35,36 As mentioned above, herbacetin glycosides and kaempferol are among the compounds isolated from Rhodiola that possess antioxidant and anti-inflammatory properties. 19 Moreover, Rhodiola extract contains other antioxidant compounds such as p-tyrosol, organic acids (gallic and caffeic acids), and flavonoids (catechins and proanthocyanidins).…”

Nitrite Signaling in Pulmonary Hypertension: Mechanisms of Bioactivation, Signaling, and Therapeutics

“…PAH is a multifactorial process, but early disease is related to a dysregulation of critical vasodilator pathways (downregulation of nitric oxide [NO] and prostaglandin signaling) and vasoconstrictor pathways (upregulation of endothelin-1 and reactive oxygen species [ROS] signaling) (75). PAH is associated with decreased bioavailability and responsiveness of NO (14,32).…”

“…2). Although the expression levels of endothelial NOS (eNOS) in patients with PAH can vary from high to normal, the formation of NO and eNOS activity have been found reduced in patients with idiopathic PAH (75). Recent studies suggest that eNOS uncoupling may relate to impaired NO production in PAH, a process by which the enzyme transfers electrons from the NOS reductase domain to the oxygenase domain and diverted to molecular oxygen forming superoxide rather than NO.…”