Serotonin and chronic hypoxic pulmonary hypertension activate a NADPH oxidase 4 and TRPM2 dependent pathway for pulmonary arterial smooth muscle cell proliferation and migration

Song, Jia; Zheng, Si Yi; He, Rui; Gui, Long; Lin, Mo Jun; Sham, James S.K.

doi:10.1016/j.vph.2021.106860

Cited by 13 publications

(22 citation statements)

References 59 publications

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“…The subsequent nitrosative stress may be potential triggers of the onset of PH (Tanaka et al, 2018). However, role of catalase in PH is controversial, it has been reported that chronic hypoxia induced reactive oxygen species production could be reversed by catalase (Song et al, 2021). Mice with mitochondrial targeted catalase overexpression attenuated hypoxia-induced PH and proliferative markers (Adesina et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Identification of Hypoxia Induced Metabolism Associated Genes in Pulmonary Hypertension

Xie

Zhang

et al. 2021

Front. Pharmacol.

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Objective: Pulmonary hypertension (PH) associated with hypoxia and lung disease (Group 3) is the second most common form of PH and associated with increased morbidity and mortality. This study was aimed to identify hypoxia induced metabolism associated genes (MAGs) for better understanding of hypoxic PH.Methods: Rat pulmonary arterial smooth muscle cells (PASMCs) were isolated and cultured in normoxic or hypoxic condition for 24 h. Cells were harvested for liquid chromatography-mass spectrometry analysis. Functional annotation of distinguishing metabolites was performed using Metaboanalyst. Top 10 enriched metabolite sets were selected for the identification of metabolism associated genes (MAGs) with a relevance score >8 in Genecards. Transcriptomic data from lungs of hypoxic PH in mice/rats or of PH patients were accessed from Gene Expression Omnibus (GEO) database or open-access online platform. Connectivity Map analysis was performed to identify potential compounds to reverse the metabolism associated gene profile under hypoxia stress. The construction and module analysis of the protein-protein interaction (PPI) network was performed. Hub genes were then identified and used to generate LASSO model to determine its accuracy to predict occurrence of PH.Results: A total of 36 altered metabolites and 1,259 unique MAGs were identified in rat PASMCs under hypoxia. 38 differentially expressed MAGs in mouse lungs of hypoxic PH were revealed, with enrichment in multi-pathways including regulation of glucose metabolic process, which might be reversed by drugs such as blebbistatin. 5 differentially expressed MAGs were displayed in SMCs of Sugen 5416/hypoxia induced PH rats at the single cell resolution. Furthermore, 6 hub genes (Cat, Ephx1, Gpx3, Gstm4, Gstm5, and Gsto1) out of 42 unique hypoxia induced MAGs were identified. Higher Cat, Ephx1 and lower Gsto1 were displayed in mouse lungs under hypoxia (all p < 0.05), in consistent with the alteration in lungs of PH patients. The hub gene-based LASSO model can predict the occurrence of PH (AUC = 0.90).Conclusion: Our findings revealed six hypoxia-induced metabolism associated hub genes, and shed some light on the molecular mechanism and therapeutic targets in hypoxic PH.

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Section: Discussionmentioning

confidence: 99%

Identification of Hypoxia Induced Metabolism Associated Genes in Pulmonary Hypertension

Xie

Zhang

et al. 2021

Front. Pharmacol.

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“…Moreover, NOX4 is confirmed to elevate pulmonary vascular remodeling in the HPH rodent models [51,52]. It is worth noting that the hyperproliferation and migration of PASMCs are closely related to an increase in NOX4-derived ROS [13,14,53]. In agreement with the evidence, the expression of NOX4 at mRNA and protein levels was upregulated in PASMCs under hypoxia conditions, while small interfering RNA-(siRNA-) mediated NOX4 silencing decreased ROS production, cell proliferation, and apoptosis resistance [12,14,54].…”

Section: Discussionmentioning

confidence: 66%

“…Numerous pieces of evidence have demonstrated that oxidative stress contributes to PASMC proliferation in hypoxia-induced PH when excessive reactive oxygen species (ROS) are generated [10,11]. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is one of the predominant sources of incremental ROS accumulation that can result in hyperproliferation and migration of PASMCs in HPH [12][13][14]. HIF-1α was reported to be essential in facilitating the increase of NOX4 in PASMCs under hypoxia conditions [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Lycopene Ameliorates Hypoxic Pulmonary Hypertension via Suppression of Oxidative Stress

Wang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Hypoxic pulmonary hypertension (HPH) is a progressive cardiopulmonary system disease characterized by pulmonary vascular remodeling. Its occurrence and progression are closely related to oxidative stress. Lycopene, extracted from red vegetables and fruits, exhibits a particularly high antioxidant capacity that is beneficial for cardiovascular diseases. Nevertheless, the role and mechanism of lycopene in HPH remain unknown. Here, we found that lycopene reversed the elevated right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary vascular remodeling induced by hypoxia in rats. In vitro, lycopene caused lower proliferation and migration of PASMCs, with higher apoptosis. Consistent with the antiproliferative result of lycopene on hypoxic PASMCs, the hippo signaling pathway associated with cell growth was activated. Furthermore, lycopene reduced malondialdehyde (MDA) levels and enhanced superoxide dismutase (SOD) activity in the lungs and serum of rats under hypoxia conditions. The expression of NOX4 in the lungs was also significantly decreased. Hypoxic PASMCs subjected to lycopene showed decreased reactive oxygen species (ROS) production and NOX4 expression. Importantly, lycopene repressed HIF-1α expression both in the lungs and PASMCs in response to hypoxia in the absence of a significant change of HIF-1α mRNA. Compared with 2ME2 (a HIF-1α inhibitor) alone treatment, lycopene treatment did not significantly change PASMC proliferation, NOX4 expression, and ROS production after 2ME2 blocked HIF-1α, suggesting the inhibitory effect of lycopene on HIF-1α-NOX4-ROS axis and the targeted effect on HIF-1α. After CHX blocked protein synthesis, lycopene promoted the protein degradation of HIF-1α. MG-132, a proteasome inhibitor, notably reversed the decrease in HIF-1α protein level induced by lycopene in response to hypoxia. Therefore, lycopene suppressed hypoxia-induced oxidative stress through HIF-1α-NOX4-ROS axis, thereby alleviating HPH. Our findings will provide a new research direction for clinical HPH therapies.

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“…Moreover, recent research has connected ROS-induced activation of TRPM2 to the enhanced proliferation and migration of PASMC in a model of chronic hypoxic pulmonary hypertension [ 169 ]. Increased concentrations of intracellular ROS also triggered the opening of TRPV4 in microvascular endothelial cells inducing endothelial dysfunction and the development of PAH in a rat model [ 170 ].…”

Section: Trp Channels and The Development Of Pulmonary Arterial Hyper...mentioning

confidence: 99%

Transient Receptor Potential (TRP) Channels in Airway Toxicity and Disease: An Update

Müller¹,

Alt²,

Rajan³

et al. 2022

Cells

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Our respiratory system is exposed to toxicants and pathogens from both sides: the airways and the vasculature. While tracheal, bronchial and alveolar epithelial cells form a natural barrier in the airways, endothelial cells protect the lung from perfused toxic compounds, particulate matter and invading microorganism in the vascular system. Damages induce inflammation by our immune response and wound healing by (myo)fibroblast proliferation. Members of the transient receptor potential (TRP) superfamily of ion channel are expressed in many cells of the respiratory tract and serve multiple functions in physiology and pathophysiology. TRP expression patterns in non-neuronal cells with a focus on TRPA1, TRPC6, TRPM2, TRPM5, TRPM7, TRPV2, TRPV4 and TRPV6 channels are presented, and their roles in barrier function, immune regulation and phagocytosis are summarized. Moreover, TRP channels as future pharmacological targets in chronic obstructive pulmonary disease (COPD), asthma, cystic and pulmonary fibrosis as well as lung edema are discussed.

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Serotonin and chronic hypoxic pulmonary hypertension activate a NADPH oxidase 4 and TRPM2 dependent pathway for pulmonary arterial smooth muscle cell proliferation and migration

Cited by 13 publications

References 59 publications

Identification of Hypoxia Induced Metabolism Associated Genes in Pulmonary Hypertension

Identification of Hypoxia Induced Metabolism Associated Genes in Pulmonary Hypertension

Lycopene Ameliorates Hypoxic Pulmonary Hypertension via Suppression of Oxidative Stress

Transient Receptor Potential (TRP) Channels in Airway Toxicity and Disease: An Update

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