Antioxidant Therapy for the Treatment of Pulmonary Hypertension

Abstract

Substantial experimental evidence suggests the usefulness of antioxidants for the treatment of various forms of pulmonary hypertension. However, no recommendations have yet been made if patients with pulmonary hypertension should receive pharmacologic and/or dietary antioxidants. Our understanding of antioxidants has evolved greatly over the last two decades, from the primitive use of natural antioxidant vitamins to the modulation of vascular oxidases, such as NAD(P)H oxidases. These oxidases and their products not only regulate pulmonary vascular tone and intimal and smooth muscle thickening, but also modulate the adaptation of the right ventricle to increased afterload. It is important that well-designed randomized clinical trials be conducted to test the importance of oxidase-reactive oxygen species activation in the pathogenesis and treatment of pulmonary hypertension. The purpose of this Forum on Pulmonary Hypertension is to summarize the available preclinical information, which may aid in designing and conducting future randomized clinical trials for evaluating the efficacy of antioxidants for the treatment of pulmonary hypertension. The complexity of oxidative pathways contributed to the tremendous difficulties and challenges in selecting agents, doses, and designing clinical trials. Further studies using human, animal, and cell culture models may be needed to define optimal trials. This Forum on Pulmonary Hypertension should stimulate new thinking and provide essential background information to better define the challenges of developing successful randomized clinical trials in the near future. Antioxid. Redox Signal. 18, 1723-1726. Many studies suggest a pathogenic role for reactive oxygen species (ROS) and oxidative stress in pulmonary arterial hypertension (PAH). Experimental animal models have demonstrated the effectiveness of various antioxidant therapeutics in modulating PAH development and their progression. Moreover, PAH patients have increased oxidative stress and upregulation of critical oxidase enzyme systems. Despite substantial experimental evidence suggesting the usefulness of antioxidants for the treatment of pulmonary hypertension at various aspects of this disease (Fig. 1), it is unclear if patients with pulmonary hypertension should receive pharmacologic and/or dietary antioxidants. Furthermore, our conceptual understanding of antioxidants has evolved greatly over the last two decades, from the primitive use of natural antioxidant vitamins, with very low radical reactivities, to the current emphasis on the modulation of vascular oxidases, such as xanthine oxidase, NAD(P)H oxidases, and pathological mitochondrial ROS formation. These oxidases and their products appear to regulate not only pulmonary vascular tone and maladaptive intimal and smooth muscle proliferation, but also modulate the adaptation of the right ventricle to chronically increased afterload stress. It is important that well-designed randomized clinical trials be conducted to test the importance of oxidase-ROS acti...

Pulmonary Arterial Hypertension

“…These oxidases are the subject of current active research and include the NADPH oxidase (Nox) family, xanthine and aldehyde oxidases, an “uncoupled” eNOS, and dysfunctional mitochondria. 55, 56 For example, increased expression of NADPH oxidase isoform 4 (Nox4) in the vasculature of patients with PAH may disrupt canonical NO signaling through a number of pathways. ROS produced from Nox4 and other oxidases can critically alter the balance of NADP + /NADPH and tetrahydrobiopterin to dihydrobiopterin (BH 4 /BH 2 ), which maintain cellular redox balance.…”

Oxidative Stress Is Associated With Increased Pulmonary Artery Systolic Pressure in Humans

“…44 This may have been partly secondary to the lack of well-designed randomized controlled clinical trials with therapies targeted to OS pathways as almost all studies to date have investigated the effect of non-targeted antioxidant compounds in experimental models of PH with overall mixed results. 45, 46 …”

Novel putative pharmacological therapies to protect the right ventricle in pulmonary hypertension: a review of current literature

“…Oxidative stress is characterized by the increased production of oxidants such as ROS (including superoxide anion radical, hydrogen peroxide and hydroxyl radical) and insufficient levels/activities of antioxidant enzymes (including superoxide dismutase, catalase and glutathione peroxidase) (Bowers et al, ; Suzuki et al, ; Wong et al, ; Voelkel et al, ) (Figure ). It is well known that a disease such as PH enhances the production of ROS and reduces antioxidant enzyme activity (Demarco et al, ; Wong et al, ; Voelkel et al, ).…”

“…This is important, because at this time point, the disease is at a late stage and it therefore suggests that pharmacological antioxidant treatment may be effective in late‐stage PH. Although the authors of both studies described above did not directly measure markers of oxidative stress, it is appropriate to speculate that the beneficial effects of resveratrol may be due to its potent antioxidant properties (Suzuki et al, ; Wong et al, ; Voelkel et al, ).…”

“…It is important to mention that even though oxidative stress is detrimental in the pulmonary vasculature and in cardiac remodelling, its actions in the heart are somewhat complex (Suzuki et al, ; Wong et al, ; Voelkel et al, ). ROS play two major roles in the heart, which include its ability to cause injury to cell components as well as antioxidant defence (Suzuki et al, ; Wong et al, ; Voelkel et al, ). Piantadosi et al showed that ROS play a crucial role in antioxidant‐induced cardiac mitochondrial biogenesis by liberating, stabilizing and translocating the transcription factor, nuclear respiratory factor‐2 (NRF2), to the nucleus (Piantadosi et al, ).…”