Reactive oxygen species and antioxidants in pulmonary hypertension

Abstract

Significance: Pulmonary hypertension is a devastating disorder without any available treatment strategies that satisfactorily promote the survival of patients. The identification of new therapeutic strategies to treat patients with pulmonary hypertension is warranted.

Recent advances: Human studies have provided evidence that there is increased oxidative stress (lipid peroxidation, protein oxidation, DNA oxidation, and the depletion of small-molecule antioxidants) in patients with pulmonary hypertension. A variety of compounds with antioxidant properties have been shown to have beneficial therapeutic effects in animal models of pulmonary hypertension, possibly supporting the hypothesis that reactive oxygen species (ROS) are involved in the progression of pulmonary hypertension. Thus, understanding the molecular mechanisms of ROS actions could contribute to the development of optimal, antioxidant-based therapy for human pulmonary hypertension. One such mechanism includes action as a second messenger during cell-signaling events, leading to the growth of pulmonary vascular cells and right ventricular cells.

Critical issues: The molecular mechanisms behind promotion of cell signaling for pulmonary vascular cell growth and right ventricular hypertrophy by ROS are not well understood. Evidence suggests that iron-catalyzed protein carbonylation may be involved.

Future directions: Understanding precise mechanisms of ROS actions should be useful for designing preclinical animal experiments and human clinical trials of the use of antioxidants and/or other redox compounds in the treatment of pulmonary hypertension.

FIG. 1.

Evidence for the occurrence of oxidative stress in human pulmonary hypertension.

FIG. 2.

Antioxidants that have been shown to inhibit pulmonary hypertension in experimental models.

FIG. 3.

Proposed reactive oxygen species (ROS)-dependent signaling pathways for serotonin (5-HT)-induced GATA4 activation in pulmonary artery smooth muscle cells. 5-HT has been shown to produce hydrogen peroxide (H₂O₂) via 5-HT transporter (SERT) either by activating NAD(P)H oxidase (NOX) or by activating monoamine oxidase-A (MAO-A). H₂O₂, in turn, (i) activates MEK to phosphorylate ERK and/or (ii) activates RhoA/Rho kinase (ROCK) pathway, facilitating ERK nuclear translocation. In the nucleus, ERK then phosphorylates and activates GATA4 (–27, 45).

FIG. 4.

Chemical structures of native and carbonylated forms of protein amino acids that can be carbonylated.

FIG. 5.

Proposed ROS signaling mechanism for GATA4 activation in the right ventricle (RV) in response to pulmonary hypertension (PH). In right ventricular myocytes, CCAAT box plays an important role in the transcription of the Gata4 gene and is regulated by CCAAT-binding factor/nuclear factor-Y (CBF/NF-Y) transcription factor. CBF/NF-Y is inactive when annexin A1 is bound. Signaling stimuli in response to PH and pressure overload liberate CBF/NF-Y as an active form via the production of ROS, which in turn carbonylate annexin A1. Carbonylated annexin A1 gets degraded by proteasomes. Active CBF/NF-Y binds to CCAAT box and promotes gene transcription and activation of GATA4, leading to right ventricular hypertrophy. Adapted from Park et al. (32).

FIG. 6.

A proposed mechanism involving oxidant signaling for disease progression and possible therapeutic strategies. Receptor interactions with various ligands such as endothelin-1 (ET-1), 5-HT, and platelet-derived growth factor (PDGF) activate the generation of ROS, which in turn promote oxidation of target signaling molecules, leading to the progression of various diseases, including pulmonary vascular and right ventricular remodeling. Selective inhibition of these oxidant-signaling components may allow for optimal antioxidant-based therapeutic strategies, which specifically eliminate unwanted actions of ROS.