The cancer theory of pulmonary arterial hypertension

Boucherat, Olivier; Vitry, Géraldine; Trinh, Isabelle; Paulin, Roxane; Provencher, Steeve; Bonnet, Sébastien

doi:10.1177/2045893217701438

Cited by 166 publications

(149 citation statements)

References 155 publications

(198 reference statements)

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“…There was also a 4-fold increase in migration and an approximately 25% decrease in apoptosis of MCTPASMCs. These results indicated that the homeostasis of PASMC proliferation, migration and apoptosis was dramatically interrupted in MCT-induced PAH, which coincided to some extent with the features of the quasi-cancerous cells [45][46][47][48][49]. Our data revealed that CaN/NFAT signaling was over-activated in MCT-PASMCs.…”

Section: Discussionmentioning

confidence: 49%

Calcineurin/NFAT Signaling Modulates Pulmonary Artery Smooth Muscle Cell Proliferation, Migration and Apoptosis in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Pulmonary arterial hypertension (PAH) is a severe and debilitating disease characterized by remodeling of the pulmonary vessels, which is driven by excessive proliferation and migration and apoptosis resistance in pulmonary artery smooth muscle cells (PASMCs). The calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) signaling pathway is the most important downstream signaling pathway of store-operated Ca²⁺ entry (SOCE), which is increased in PAH. CaN/NFAT has been reported to contribute to abnormal proliferation in chronic hypoxia (CH)-induced PAH. However, the effect of CaN/NFAT signaling on PASMC proliferation, migration and apoptosis in monocrotaline (MCT)-induced PAH remains unclear. Methods: PAH rats were established by a single intraperitoneal injection of MCT for 21 days. PASMCs were isolated and cultured in normal and MCT-induced PAH Sprague-Dawley rat. PASMCs were treated with CsA targeting CaN and siRNA targeting NFATc2-4 gene respectively by liposome. We investigated the expression of calcineurin/NFAT signaling by immunofluorescence, qRT-PCR and Western blotting methods. Cell proliferation was monitored using MTS reagent or by assessing proliferating cell nuclear antigen (PCNA) expression. Cell apoptosis was evaluated with an Annexin V - FITC/propidium iodide (PI) apoptosis kit by flow cytometry. PASMC migration was assessed with a Transwell chamber. Results: MCT successfully induced PAH and pulmonary vascular remodeling in rats. CaN phosphatase activity and nuclear translocation of NFATc2-4 were increased in PASMCs derived from MCT-treated rats. In addition, CaNBβ/NFATc2-4 expression was amplified at the mRNA and protein levels. PASMC proliferation and migration were markedly inhibited in a dosedependent manner by cyclosporin A (CsA). Furthermore, siRNA targeting NFATc2 and NFATc4 attenuated the excessive proliferation and migration and apoptosis resistance in PASMCs derived from both CON and MCT-treated rats, while NFATc3 knockdown specifically affected MCT-PASMCs. Conclusion: Our results demonstrate that CaN/NFAT signaling is activated and involved in the modulation of PASMC proliferation, migration and apoptosis in MCT-induced PAH.

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Section: Discussionmentioning

confidence: 49%

Calcineurin/NFAT Signaling Modulates Pulmonary Artery Smooth Muscle Cell Proliferation, Migration and Apoptosis in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats

Liu

et al. 2018

Cell Physiol Biochem

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“…Interestingly, patients that developed lung cancer exhibited increased IL‐6 levels, and these were lowered following treatment with canakinumab (Ridker et al ., ). These observations parallel the pathobiology of PH which is characterized by marked increases in circulating IL‐6 and is increasingly thought of as a hyper‐proliferative, anti‐apoptotic, metabolically disturbed disorder (Boucherat et al ., ). Notwithstanding, there was a higher incidence of fatal infection and sepsis in those patients receiving canakinumab compared to placebo (Ridker et al ., ).…”

Section: Inflammasomes In Pulmonary Hypertensionmentioning

confidence: 97%

Inflammasomes: a novel therapeutic target in pulmonary hypertension?

Scott

Kemp-Harper

Hobbs

2018

British J Pharmacology

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Pulmonary hypertension (PH) is a rare, progressive pulmonary vasculopathy characterized by increased mean pulmonary arterial pressure, pulmonary vascular remodelling and right ventricular failure. Current treatments are not curative, and new therapeutic strategies are urgently required. Clinical and preclinical evidence has established that inflammation plays a key role in PH pathogenesis, and recently, inflammasomes have been suggested to be central to this process. Inflammasomes are important regulators of inflammation, releasing the pro-inflammatory cytokines IL-1β and IL-18 in response to exogenous pathogen- and endogenous damage-associated molecular patterns. These cytokines are elevated in PH patients, but whether this is a consequence of inflammasome activation remains to be determined. This review will briefly summarize current PH therapies and their pitfalls, introduce inflammasomes and the mechanisms by which they promote inflammation and, finally, highlight the preclinical and clinical evidence for the potential involvement of inflammasomes in PH pathobiology and how they may be targeted therapeutically.

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“…It is meaningful and urgent to clarify the pathogenesis of PH. In comparison with previous belief that vasoconstriction acts as a vital role in PH pathogenesis, it is more clearly constituted that pulmonary vascular remodeling is the key 3 causal factor of PH, which is characterized by excessive proliferation and resistance to apoptosis of PASMC and pulmonary artery endothelial cells (PAEC) 2 . PASMC has been proved to play an important role in the development of various types of pulmonary hypertension.…”

Section: Introductionmentioning

confidence: 85%

Short-chain fatty acid-Butyrate ameliorates hypoxia-induced pulmonary hypertension in rat

He¹,

Zhu²,

Zhu³

et al. 2019

Preprint

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Background: Gut Microbiome can produce numerous metabolites which may be absorbed into the circulation and play a critical role in the development of diseases. Our study wants to find out the roles of faecal microbiota and its metabolite in the development of pulmonary hypertension.Methods: SD rats were expose to either normoxia (Control, n=8) or chronic hypoxia (10% O2) (n=16).Rats in chronic hypoxia were randomly received sodium butyrate (500 mg/kg) (n=8) or volumematched saline (n=8) once a day. Rats in normoxia condition also received volume-matched saline once a day. RVSP and lung vascular features were assessed after 3 week's treatment. Rats' fecal samples were collected and analyzed by GCMS and 6S/18S Amplicon Sequencing. Activation of HIF-1α, HMGB2, TLR4, TNF-α, HDAC5 and PCNA was assessed using Western blot analysis. The effect of sodium butyrate on proliferation of pulmonary artery smooth muscle cell, induced by PDGF or hypoxia (1% O2), was evaluated by CCK-8, EDU assay and wound healing assay. Results: Hypoxia significantly increased RVSP and induced a significant decrease in butyrateproducing bacteria, but a slight decrease of SCFAs without statistic difference. Administration of sodium butyrate remarkably attenuated the RVSP and improved lung vascular features. Decreased expression of HDAC5, PCNA, HIF-1α, HMGB2, TLR4, TNF-α and inhibited proliferation of PASMC were found in rats or cells with sodium butyrate. Conclusions: Decreased butyrate-producing bacteria may contribute to the development of PH, and sodium butyrate supplement can effectively attenuate hypoxia-induced PH in rats probably by inhibiting the proliferation and migration of PASMC. EDU: 5-Ethynyl-2 ' -deoxyuridine SCFAs: Short chain fatty acids MCT: Monocrotaline NS: Normal saline SB: Sodium Butyrate Declarations Ethics approval and consent to participateThe rats experiment protocol was approved by the Animal Research Committee

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The cancer theory of pulmonary arterial hypertension

Cited by 166 publications

References 155 publications

Calcineurin/NFAT Signaling Modulates Pulmonary Artery Smooth Muscle Cell Proliferation, Migration and Apoptosis in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats

Calcineurin/NFAT Signaling Modulates Pulmonary Artery Smooth Muscle Cell Proliferation, Migration and Apoptosis in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats

Inflammasomes: a novel therapeutic target in pulmonary hypertension?

Short-chain fatty acid-Butyrate ameliorates hypoxia-induced pulmonary hypertension in rat

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