Redox Regulation, Oxidative Stress, and Inflammation in Group 3 Pulmonary Hypertension

Rudyk, Olena; Aaronson, Philip I.

doi:10.1007/978-3-030-63046-1_13

Cited by 9 publications

(9 citation statements)

References 201 publications

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“…[ 33 ] In the lung tissues of PAH patients or animals, the levels of interleukins, MCP‐1, VEGF, TNF‐α and CRP were significantly upregulated. [ 34 ] Moreover, IL‐1β and IL‐6 are associated with poor prognosis in patients with PAH.…”

Section: Discussionmentioning

confidence: 99%

Matrine alleviates hypoxia‐induced inflammation and pulmonary vascular remodelling via RPS5/NF‐κB signalling pathway

Li,

Ying,

et al. 2023

J Biochem & Molecular Tox

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Hypoxia‐induced vasoconstriction and vascular remodelling are the main pathological features of hypoxic pulmonary arterial hypertension (HPAH), and inflammation is participated in the occurrence of pulmonary vascular remodelling (PVR). Matrine is an alkaloid with the effects of anti‐inflammation, antifibrosis and antitumour. But, few studies have explored the role of matrine in regulating PVR, and the related mechanisms are still unknown. In this study, we found that hypoxia‐induced pulmonary artery smooth muscle cells (PASMCs) proliferation and inhibited its apoptosis, reduced the expression of ribosomal protein s5 and activated the nuclear factor kappa‐B (NF‐κB) signalling. Matrine, sildenafil and NF‐κB inhibitor Bay 11‐7082 could reverse these changes and impel the cell cycle in phase S retardation, and reduced the expression of p50, p65, proliferating cell nuclear antigen (PCNA), Bcl‐2. In addition, matrine could lower right ventricular systolic pressure and mean pulmonary artery pressure of rats, α‐smooth muscle actin and PCNA expression in pulmonary artery media, the levels of tumor necrosis factor‐α and interleuki‐1β, thus improved hypoxia‐induced PVR. This study indicated that matrine could alleviate inflammation and improve PVR through reversing the imbalance of proliferation and apoptosis of PASMCs, thus it had a therapeutic effect on HPAH.

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Section: Discussionmentioning

confidence: 99%

Matrine alleviates hypoxia‐induced inflammation and pulmonary vascular remodelling via RPS5/NF‐κB signalling pathway

Li,

Ying,

et al. 2023

J Biochem & Molecular Tox

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“…30 In addition, our previous work shows that the formation of a kinaseactivating intermolecular disulfide bond in PKGIα (protein kinase G Iα) promotes vasodilation 31 and attenuates endothelial-to-mesenchymal transition to provide protection against the development of severe PH. 16,24 Furthermore, we showed an adaptive intermolecular bond in PKARIα (protein kinase A regulatory subunit RIα) regulates angiogenesis 32 and promotes systemic vasodilation, 33 although follow-up work is required to address the role of this kinase in PH.…”

Section: Novelty and Significancementioning

confidence: 99%

Cyclin D-CDK4 Disulfide Bond Attenuates Pulmonary Vascular Cell Proliferation

Knight,

Abis,

Kaur

et al. 2023

Circulation Research

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Background: Pulmonary hypertension (PH) is a chronic vascular disease characterized, among other abnormalities, by hyperproliferative smooth muscle cells and a perturbed cellular redox and metabolic balance. Oxidants induce cell cycle arrest to halt proliferation; however, little is known about the redox-regulated effector proteins that mediate these processes. Here, we report a novel kinase-inhibitory disulfide bond in cyclin D-CDK4 (cyclin-dependent kinase 4) and investigate its role in cell proliferation and PH. Methods: Oxidative modifications of cyclin D-CDK4 were detected in human pulmonary arterial smooth muscle cells and human pulmonary arterial endothelial cells. Site-directed mutagenesis, tandem mass-spectrometry, cell-based experiments, in vitro kinase activity assays, in silico structural modeling, and a novel redox-dead constitutive knock-in mouse were utilized to investigate the nature and definitively establish the importance of CDK4 cysteine modification in pulmonary vascular cell proliferation. Furthermore, the cyclin D-CDK4 oxidation was assessed in vivo in the pulmonary arteries and isolated human pulmonary arterial smooth muscle cells of patients with pulmonary arterial hypertension and in 3 preclinical models of PH. Results: Cyclin D-CDK4 forms a reversible oxidant-induced heterodimeric disulfide dimer between C7/8 and C135, respectively, in cells in vitro and in pulmonary arteries in vivo to inhibit cyclin D-CDK4 kinase activity, decrease Rb (retinoblastoma) protein phosphorylation, and induce cell cycle arrest. Mutation of CDK4 C135 causes a kinase-impaired phenotype, which decreases cell proliferation rate and alleviates disease phenotype in an experimental mouse PH model, suggesting this cysteine is indispensable for cyclin D-CDK4 kinase activity. Pulmonary arteries and human pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension display a decreased level of CDK4 disulfide, consistent with CDK4 being hyperactive in human pulmonary arterial hypertension. Furthermore, auranofin treatment, which induces the cyclin D-CDK4 disulfide, attenuates disease severity in experimental PH models by mitigating pulmonary vascular remodeling. Conclusions: A novel disulfide bond in cyclin D-CDK4 acts as a rapid switch to inhibit kinase activity and halt cell proliferation. This oxidative modification forms at a critical cysteine residue, which is unique to CDK4, offering the potential for the design of a selective covalent inhibitor predicted to be beneficial in PH.

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“…Redox imbalance has been indicated as a causal factor of a variety of disorders such as cancer (263)(264)(265) and hypertension (266) with translational significance. Besides, reactive oxygen and nitrogen species (RONS) are also important signaling molecules with known roles on normal function regulation such as insulin and growth factor signaling (267).…”

Section: Trends In Omics Technology Developmentmentioning

confidence: 99%

Advances and Trends in Omics Technology Development

2022

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The human history has witnessed the rapid development of technologies such as high-throughput sequencing and mass spectrometry that led to the concept of “omics” and methodological advancement in systematically interrogating a cellular system. Yet, the ever-growing types of molecules and regulatory mechanisms being discovered have been persistently transforming our understandings on the cellular machinery. This renders cell omics seemingly, like the universe, expand with no limit and our goal toward the complete harness of the cellular system merely impossible. Therefore, it is imperative to review what has been done and is being done to predict what can be done toward the translation of omics information to disease control with minimal cell perturbation. With a focus on the “four big omics,” i.e., genomics, transcriptomics, proteomics, metabolomics, we delineate hierarchies of these omics together with their epiomics and interactomics, and review technologies developed for interrogation. We predict, among others, redoxomics as an emerging omics layer that views cell decision toward the physiological or pathological state as a fine-tuned redox balance.

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Redox Regulation, Oxidative Stress, and Inflammation in Group 3 Pulmonary Hypertension

Cited by 9 publications

References 201 publications

Matrine alleviates hypoxia‐induced inflammation and pulmonary vascular remodelling via RPS5/NF‐κB signalling pathway

Matrine alleviates hypoxia‐induced inflammation and pulmonary vascular remodelling via RPS5/NF‐κB signalling pathway

Cyclin D-CDK4 Disulfide Bond Attenuates Pulmonary Vascular Cell Proliferation

Advances and Trends in Omics Technology Development

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