Antioxidants for the Treatment of Patients with Severe Angioproliferative Pulmonary Hypertension?

Voelkel, Norbert F.; Bogaard, Harm Jan; Husseini, Aysar Al; Farkas, László; Gomez-Arroyo, José; Natarajan, Ramesh

doi:10.1089/ars.2012.4828

Cited by 38 publications

(29 citation statements)

References 56 publications

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“…Hypoxic stress and HIF-1α overexpression have been related to reactive oxygen species (ROS) production. 34,35 Moreover, there are huge evidences showing that H 2 0 2 emission from mitochondria during hypoxia regulates cellular responses to hypoxia. 36,37 In agreement with previous data, results from the present study showed that one of the phenotypic changes that hypoxia induces in hVSMC is an increased ROS production.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Induces Metalloproteinase-9 Activation and Human Vascular Smooth Muscle Cell Migration Through Low-Density Lipoprotein Receptor–Related Protein 1–Mediated Pyk2 Phosphorylation

Revuelta‐López

Castellano

Roura

et al. 2013

ATVB

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Objective— Hypoxia disturbs vascular function by promoting extracellular matrix remodeling. Extracellular matrix integrity and composition are modulated by metalloproteinases (MMPs). Our aim was to investigate the role of low-density lipoprotein receptor–related protein 1 (LRP1) in regulating MMP-9/MMP-2 activation and vascular smooth muscle cells (VSMCs) migration in response to hypoxia, and to elucidate the LRP1-signaling pathways involved in this process. Approach and Results— Western blot analysis showed that hypoxia induced a sustained phosphorylation of proline-rich tyrosine kinase 2 concomitantly with LRP1 overexpression in human VSMCs (hVSMCs). Deletion of LRP1 using small-interfering RNA technology or treatment of hVSMCs with the Src family kinase inhibitor PP2 impaired hypoxia-induced phosphorylation of proline-rich tyrosine kinase 2 levels. Coimmunoprecipitation experiments showed that the higher amounts of phosphorylation of proline-rich tyrosine kinase 2/LRP1β immunoprecipitates in hypoxic hVSMCs were abolished in PP2-treated hVSMCs. Both LRP1 silencing and PP2 treatment were highly effective in the prevention of hypoxia-induced MMP-9 activation and hVSMC migration. Cellular subfractionation experiments revealed that PP2 effects may be caused by impairment of hypoxia-induced nuclear factor-κβ translocation to the nucleus. ELISA measurements showed that LRP1 silencing but not PP2 treatment increased interleukin-1β, interleukin-6, and monocyte chemoattractant protein-1 secretion by hypoxic hVSMCs. Conclusions— Our findings determine a crucial role of LRP1-mediated Pyk2 phosphorylation on hypoxia-induced MMP-9 activation and hVSMC migration and therefore in hypoxia-induced vascular remodeling. Both LRP1 silencing and PP2 treatments also influence hypoxia-induced proinflammatory effects in hVSMCs. Therefore, further studies are required to establish therapeutical strategies that efficiently modulate vascular remodeling and inflammation associated with hypoxia-vascular diseases.

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Section: Discussionmentioning

confidence: 99%

Hypoxia Induces Metalloproteinase-9 Activation and Human Vascular Smooth Muscle Cell Migration Through Low-Density Lipoprotein Receptor–Related Protein 1–Mediated Pyk2 Phosphorylation

Revuelta‐López

Castellano

Roura

et al. 2013

ATVB

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“…Oxidized guanosine and 3-nitrotyrosine levels have also been demonstrated to be elevated in experimental models of PAH and in lung tissue from patients. [29][30][31] We and others have shown that disruption of extracellular superoxide dismutase (EC-SOD), either globally or in specific cell populations, results in exacerbation of experimental PAH, with accompanying increases in markers of oxidant injury, and that enhancing EC-SOD activity ameliorates disease. [32][33][34] To help solidify a causative link between oxidant injury and PAH, we have shown that driving mitochondrial oxidant injury (quantified by measurement of lipid peroxidation products) using brief daily exposure to hyperoxia worsens PAH in BMPR2-mutant mice and also drives dysregulation of glucose homeostasis, suggesting a link between oxidant injury and cellular metabolism.…”

Section: Oxidant Injury In Pahmentioning

confidence: 99%

Redox Biology in Pulmonary Arterial Hypertension (2013 Grover Conference Series)

Fessel

West

2015

Pulm. circ.

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Through detailed interrogation of the molecular pathways that contribute to the development of pulmonary arterial hypertension (PAH), the separate but related processes of oxidative stress and cellular metabolic dysfunction have emerged as being critical pathogenic mechanisms that are as yet relatively untargeted therapeutically. In this review, we have attempted to summarize some of the important existing studies, to point out areas of overlap between oxidative stress and metabolic dysfunction, and to do so under the unifying heading of redox biology. We discuss the importance of precision in assessing oxidant signaling versus oxidant injury and why this distinction matters. We endeavor to advance the discussion of carbon-substrate metabolism beyond a focus on glucose and its fate in the cell to encompass other carbon substrates and some of the murkiness surrounding our understanding of how they are handled in different cell types. Finally, we try to bring these ideas together at the level of the mitochondrion and to point out some additional points of possible cognitive dissonance that warrant further experimental probing. The body of beautiful science regarding the molecular and cellular details of redox biology in PAH points to a future that includes clinically useful therapies that target these pathways. To fully realize the potential of these future interventions, we hope that some of the issues raised in this review can be addressed proactively.Keywords: bone morphogenetic protein receptor 2, Warburg, 3-nitrotyrosine, nitrosylation. Considered in a positive light, the intense investigative efforts into the pathogenesis of pulmonary arterial hypertension (PAH) over the past several decades can be viewed as a major success. We continue to gain more-detailed insights into the molecular mechanisms that cause and sustain disease. New therapeutics are being successfully tested and approved for human use, with more in the developmental pipeline. Emerging data suggest not only that the thoughtful and aggressive use of existing therapies has improved the quality of life and functional status for patients with PAH but also that these therapies have actually had a measurable positive impact on survival. 1 However, most investigators in the field remain driven by a lingering dissatisfaction. Although existing therapies are certainly beneficial in terms of improving functional status and quality of life and likely have a measurable survival benefit, many patients still will progress to the end points of death or need for transplantation. In tissues collected from these individuals, either at autopsy or at explantation of the diseased lungs, it appears that targeted therapies have not changed the course of the pulmonary vascular pathology.2 New drugs continue to be developed and approved for clinical use, but most of these target the same signaling pathways (e.g., prostacyclin, endothelin, and nitric oxide) as the first generation of PAH drugs. 3-5 Despite impressive progress, then, we still lack some fundame...

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“…Interestingly, upregulating nuclear factor (erythroid-derived 2)-like 2 (Nrf2 or NFE2L2) (Nrf2) activity restored ZO1 expression normalizing barrier function. Nrf2 is a transcription factor constitutively expressed in all tissues and promotes cytoprotection by activating many proteins regulating metabolism of drugs and toxins, the protection against oxidative stresses and inflammation, the stability of proteins, and the removal of damaged proteins (149). However, whether AT-1001 or zonulin neutralizing antibody prevented ALI by augmenting Nrf2 activity remains unclear.…”

Section: Endothelial Scaffoldsmentioning

confidence: 99%

Novel regulators of endothelial barrier function

Mehta

Ravindran

Kuebler

2014

American Journal of Physiology-Lung Cellular and Molecular Phys

109

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Endothelial barrier function is an essential and tightly regulated process that ensures proper compartmentalization of the vascular and interstitial space, while allowing for the diffusive exchange of small molecules and the controlled trafficking of macromolecules and immune cells. Failure to control endothelial barrier integrity results in excessive leakage of fluid and proteins from the vasculature that can rapidly become fatal in scenarios such as sepsis or the acute respiratory distress syndrome. Here, we highlight recent advances in our understanding on the regulation of endothelial permeability, with a specific focus on the endothelial glycocalyx and endothelial scaffolds, regulatory intracellular signaling cascades, as well as triggers and mediators that either disrupt or enhance endothelial barrier integrity, and provide our perspective as to areas of seeming controversy and knowledge gaps, respectively.

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Antioxidants for the Treatment of Patients with Severe Angioproliferative Pulmonary Hypertension?

Abstract: Antioxidant therapeutic strategies may be of benefit in the setting of human severe PAH. Whether antioxidant strategies affect lung vascular remodeling and/or prevent right heart failure remains to be examined.

Cited by 38 publications

References 56 publications

Hypoxia Induces Metalloproteinase-9 Activation and Human Vascular Smooth Muscle Cell Migration Through Low-Density Lipoprotein Receptor–Related Protein 1–Mediated Pyk2 Phosphorylation

Hypoxia Induces Metalloproteinase-9 Activation and Human Vascular Smooth Muscle Cell Migration Through Low-Density Lipoprotein Receptor–Related Protein 1–Mediated Pyk2 Phosphorylation

Redox Biology in Pulmonary Arterial Hypertension (2013 Grover Conference Series)

Novel regulators of endothelial barrier function

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