Resistin-like molecule β acts as a mitogenic factor in hypoxic pulmonary hypertension via the Ca2+-dependent PI3K/Akt/mTOR and PKC/MAPK signaling pathways

Tian, Heshen; Liu, Lei; Wu, Ying; Wang, Ruiwen; Jiang, Yong-Liang; Hu, Ruicheng; Zhu, Liming; Li, Linwei; Fang, Yanyan; Yang, Cheng; Ji, Lianzhi; Liu, Guoyu; Dai, Aiguo

doi:10.1186/s12931-020-01598-4

Cited by 33 publications

(25 citation statements)

References 42 publications

(30 reference statements)

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“…Emerging evidence has demonstrated that AKT signalling participates in the modulation of the phenotypic switch, proliferation, and migration of PASMCs in PAH. 25 , 26 , 27 In addition, Pitre et al showed that SYN positively promotes glioblastoma cell proliferation by promoting AKT activation. 17 As shown in Figure 5 A , SYN suppression inhibited AKT activation in hPASMCs, whereas SYN overexpression resulted in the opposite result.…”

Section: Resultsmentioning

confidence: 99%

“…Several studies have reported that the activation of AKT promotes phenotypic switch, proliferation, and migration of PASMCs, thus intensifying pulmonary vascular remodelling in PAH. 25 , 26 , 27 In addition, it has been demonstrated that SYN enhances the proliferation of glioblastoma cells via activation of the AKT signalling pathway. 17 Here, we provided direct evidence that SYN overexpression promoted hPASMCs dysfunction, and these effects were reversed by an AKT inhibitor.…”

Section: Discussionmentioning

confidence: 99%

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Synemin promotes pulmonary artery smooth muscle cell phenotypic switch in shunt‐induced pulmonary arterial hypertension

Zhou

2022

ESC Heart Failure

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Aims Although considerable progress has been made in the diagnosis and treatment of congenital heart disease‐associated pulmonary heart hypertension (CHD‐PAH), the clinical prognosis and overall survival of patients with CHD‐PAH remain poor. Therefore, the molecular pathogenesis of CHD‐PAH requires further investigation. The intermediate filament protein synemin (SYN) is reported to modulate phenotypic alterations and varicose vein development, but there is little understanding of its exact functions in CHD‐PAH. Methods and results SYN expression in the pulmonary arterioles of CHD‐PAH patients and shunt‐induced PAH rat models was evaluated using immunohistochemistry and western blot. Cell counts and Transwell migration assays were used to assess the effect of SYN on the proliferation and migration capability of human pulmonary smooth muscle cells (hPASMCs). Adeno‐associated viruses (AAVs) have been used to suppress SYN expression in the pulmonary arterioles of rats. Such rats were further used to construct a shunt‐induced PAH animal model to investigate the function of SYN in PAH and pulmonary vascular remodelling. Compared with the normal control group, SYN expression was found to be clearly up‐regulated in the remodelled pulmonary arterioles of CHD‐PAH and shunt‐induced PAH rat models. In addition, SYN suppression increased the expression of hPASMC contractile‐phenotype markers and decreased the expression of synthetic phenotype markers, in contrast to the control group. SYN suppression also dramatically attenuated the proliferation and migration capability of hPASMCs. Conversely, SYN overexpression promoted phenotypic switch, proliferation, and migration of hPASMCs, whereas these effects were notably alleviated by the protein kinase B (AKT) inhibitor MK‐2206. Furthermore, we confirmed that SYN suppression mitigated PAH and pulmonary vascular remodelling induced by high blood flow in vivo. Conclusions Our findings indicated that SYN may represent a promising therapeutic target in the treatment of CHD‐PAH.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Synemin promotes pulmonary artery smooth muscle cell phenotypic switch in shunt‐induced pulmonary arterial hypertension

Zhou

2022

ESC Heart Failure

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“… 27 After treating pulmonary arterial smooth muscle cells with exogenous recombinant RELMβ protein, the levels of phosphorylated MAPK and PKC increased, which was accompanied by a significant increase in cell viability. 14 It has been shown that erythromycin inhibits p38 MAPK phosphorylation in patients with chronic obstructive pulmonary disease, thereby improving sensitivity to glucocorticoids and reducing the level of inflammation in patients with chronic obstructive pulmonary disease. 28 The studies described above suggest that RELMβ, together with the MAPK signaling pathway, plays a vital role in regulating airway inflammation.…”

Section: Discussionmentioning

confidence: 99%

“… 13 In addition, RELMβ overexpression in mice causes hemodynamic changes, including increased mean proper ventricular systolic pressure, right heart hypertrophy, and small pulmonary artery constriction. 14 The current understanding of the mechanism by which RELMβ contributes to pulmonary inflammation is mainly derived from studies of RELMα, which is highly homologous to RELMβ. 15 In a study of rat alveolar epithelial cell inflammation in response to tobacco smoke extract, IL-8 secretion into the supernatant was correlated with RELMα expression in a time-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

The Inflammatory Response Induced by RELMβ Upregulates IL-8 and IL-1β Expression in Bronchial Epithelial Cells in COPD

Che¹,

Chen²,

Chen

et al. 2021

COPD

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Purpose Chronic obstructive pulmonary disease (COPD) is associated with a complex inflammatory regulatory network. Resistin-like molecule β (RELMβ) is highly expressed in the lungs of COPD patients. We aimed to investigate the proinflammatory effect of RELMβ on airway epithelial cells in COPD. Methods First, a GEO dataset was used to analyze the expression of the RELMβ gene in the COPD and control groups as well as the protein levels of RELMβ in the sera of outpatients with COPD and normal control subjects in our hospital. We also stimulated 16HBE bronchial epithelial cells with recombinant RELMβ protein and analyzed the expression of IL-8 and IL-1β. We upregulated and downregulated the gene expression of RELMβ in 16HBE cells and analyzed the expression of the inflammatory cytokines IL-8 and IL-1β. In addition, we also examined the mechanism by which the p38 MAPK signaling pathway contributed to the regulation of IL-8 and IL-1β expression by RELMβ. Results RELMβ expression was increased in COPD tissues in different data sets and in the serum of COPD patients in our hospital. IL-8 and IL-1β expression was also increased in COPD tissues with high RELMβ gene expression in different data sets. The RELMβ gene was mainly related to inflammatory factors and inflammatory signaling pathways in the PPI regulatory network. Experiments at the cellular level showed that RELMβ promoted the expression of the inflammatory cytokines IL-8 and IL-1β, and this regulation was mediated by the p38 MAPK signaling pathway. Conclusion RELMβ can promote the expression of the inflammatory cytokines IL-8 and IL-1β in bronchial epithelial cells of patients with COPD and exert inflammatory effects. RELMβ may be a potential target for the treatment of COPD.

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“…These serine-threonine protein kinases play critical roles in the regulation of many cellular processes including cell cycle, proliferation, and apoptosis [ 21 , 22 ]. Previous studies have shown that hypoxia promoted cell proliferation and inhibited apoptosis of PASMCs and sequentially induced pulmonary vascular remodeling via phosphorylated activation of ERK, JNK, and P38 signaling pathways [ 23 – 25 ]. Several studies have demonstrated that Notch4 was involved in the regulation of survival and migration of tumor and endothelial cells via MAPK signaling pathways [ 26 – 29 ].…”

Section: Introductionmentioning

confidence: 99%

Notch4 mediates vascular remodeling via ERK/JNK/P38 MAPK signaling pathways in hypoxic pulmonary hypertension

et al. 2022

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Background Hypoxic pulmonary hypertension (HPH) is a chronic progressive advanced disorder pathologically characterized by pulmonary vascular remodeling. Notch4 as a cell surface receptor is critical for vascular development. However, little is known about the role and mechanism of Notch4 in the development of hypoxic vascular remodeling. Methods Lung tissue samples were collected to detect the expression of Notch4 from patients with HPH and matched controls. Human pulmonary artery smooth muscle cells (HPASMCs) were cultured in hypoxic and normoxic conditions. Real-time quantitative PCR and western blotting were used to examine the mRNA and protein levels of Notch4. HPASMCs were transfected with small interference RNA (siRNA) against Notch4 or Notch4 overexpression plasmid, respectively. Cell viability, cell proliferation, apoptosis, and migration were assessed using Cell Counting Kit-8, Edu, Annexin-V/PI, and Transwell assay. The interaction between Notch4 and ERK, JNK, P38 MAPK were analyzed by co-immunoprecipitation. Adeno-associated virus 1-mediated siRNA against Notch4 (AAV1-si-Notch4) was injected into the airways of hypoxic rats. Right ventricular systolic pressure (RVSP), right ventricular hypertrophy and pulmonary vascular remodeling were evaluated. Results In this study, we demonstrate that Notch4 is highly expressed in the media of pulmonary vascular and is upregulated in lung tissues from patients with HPH and HPH rats compared with control groups. In vitro, hypoxia induces the high expression of Delta-4 and Notch4 in HPASMCs. The increased expression of Notch4 promotes HPASMCs proliferation and migration and inhibits cells apoptosis via ERK, JNK, P38 signaling pathways. Furthermore, co-immunoprecipitation result elucidates the interaction between Notch4 and ERK/JNK/P38. In vivo, silencing Notch4 partly abolished the increase in RVSP and pulmonary vascular remodeling caused by hypoxia in HPH rats. Conclusions These findings reveal an important role of the Notch4-ERK/JNK/P38 MAPK axis in hypoxic pulmonary remodeling and provide a potential therapeutic target for patients with HPH.

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Resistin-like molecule β acts as a mitogenic factor in hypoxic pulmonary hypertension via the Ca2+-dependent PI3K/Akt/mTOR and PKC/MAPK signaling pathways

Cited by 33 publications

References 42 publications

Synemin promotes pulmonary artery smooth muscle cell phenotypic switch in shunt‐induced pulmonary arterial hypertension

Synemin promotes pulmonary artery smooth muscle cell phenotypic switch in shunt‐induced pulmonary arterial hypertension

The Inflammatory Response Induced by RELMβ Upregulates IL-8 and IL-1β Expression in Bronchial Epithelial Cells in COPD

Notch4 mediates vascular remodeling via ERK/JNK/P38 MAPK signaling pathways in hypoxic pulmonary hypertension

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