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Conditioned medium from M2b macrophages modulates the proliferation, migration, and apoptosis of pulmonary artery smooth muscle cells by deregulating the PI3K/Akt/FoxO3a pathway.

ABSTRACT: Background:Immunity and inflammation are considered to be central features of pulmonary artery hypertension (PAH), in which macrophages are one of the main components of inflammatory cell infiltration around the pulmonary artery. M2b macrophages, which are different from M1 and M2 macrophages, are believed to have immunomodulatory activities and produce little fibrosis. The purpose of this study was to explore the effect of M2b macrophages on pulmonary artery smooth muscle cells (PASMCs) derived from monocrotaline-induced PAH rats. Methods:PASMCs were cultured in serum-free medium, the supernatant of M0 macrophages, or the supernatant of M2b macrophages for 24 hours. Then cell proliferation was assessed by cell counting kit-8 and cell migration ability was detected by wound healing and transwell assays. The apoptosis rate of cells was determined by TUNEL staining and annexin V-PE/7-ADD staining. Western blot was used to detect the expression of Bcl-2 family proteins, cleaved caspase-9 and PI3K/Akt/FoxO3a pathway. LY294002 (a specific inhibitor of PI3K) was used to investigate its effect on PASMCs and its relationship with M2b macrophages. Results:Conditioned medium from M2b macrophages significantly inhibited the proliferation and migration of PASMCs compared with the control group and M0 macrophage group. Furthermore, conditioned medium from M2b macrophages promote PASMC apoptosis and increased the expression of pro-apoptotic proteins Bax and cleaved caspase-9, inhibited the expression of anti-apoptotic proteins Bcl-2 and Bcl-xl. Finally, conditioned medium from M2b macrophages inhibited the PI3K/Akt/FoxO3a pathway. Inhibition of PI3K/Akt/FoxO3a pathway also significantly inhibit the proliferation, migration, and apoptosis resistance of PASMCs. Conclusion:Conditioned medium from M2b macrophages can inhibit the proliferation, migration, and apoptosis resistance of PASMCs, which may be at least partially by deregulating the PI3K/Akt/FoxO3a pathway.

SUBMITTER: Huang S

PROVIDER: S-EPMC7207208 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Conditioned medium from M2b macrophages modulates the proliferation, migration, and apoptosis of pulmonary artery smooth muscle cells by deregulating the PI3K/Akt/FoxO3a pathway.

Huang Suiqing S Yue Yuan Y Feng Kangni K Huang Xiaolin X Li Huayang H Hou Jian J Yang Song S Huang Shaojie S Liang Mengya M Chen Guangxian G Wu Zhongkai Z

PeerJ 20200505

<h4>Background</h4>Immunity and inflammation are considered to be central features of pulmonary artery hypertension (PAH), in which macrophages are one of the main components of inflammatory cell infiltration around the pulmonary artery. M2b macrophages, which are different from M1 and M2 macrophages, are believed to have immunomodulatory activities and produce little fibrosis. The purpose of this study was to explore the effect of M2b macrophages on pulmonary artery smooth muscle cells (PASMCs) ...[more]

PMID: 32411539

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Project description:This study aimed to assess the impact of conditioned medium from epidermal neural crest stem cells (EPI-NCSCs-CM) on functional recovery following spinal cord injury (SCI), while also exploring the involvement of the PI3K-AKT signaling pathway in regulating neuronal apoptosis. EPI-NCSCs were isolated from 10-day-old Sprague-Dawley rats and cultured for 48 h to obtain EPI-NCSC-CM. SHSY-5Y cells were subjected with H2O2 treatment to induce apoptosis. Cell viability and survival rates were evaluated using the CCK-8 assay and calcein-AM/PI staining. SCI contusion model was established in adult Sprague-Dawley rats to assess functional recovery, utilizing the Basso, Beattie and Bresnahan (BBB) scoring system, inclined test, and footprint observation. Neurological restoration after SCI was analyzed through electrophysiological recordings. Histological analysis included hematoxylin and eosin (H&E) staining and Nissl staining to evaluate tissue organization. Apoptosis and oxidative stress levels were assessed using TUNEL staining and ROS detection methods. Additionally, western blotting was performed to examine the expression of apoptotic markers and proteins related to the PI3K/AKT signaling pathway. EPI-NCSC-CM significantly facilitated functional and histological recovery in SCI rats by inhibiting neuronal apoptosis through modulation of the PI3K/AKT pathway. Administration of EPI-NCSCs-CM alleviated H2O2-induced neurotoxicity in SHSY-5Y cells in vitro. The use of LY294002, a PI3K inhibitor, underscored the crucial role of the PI3K/AKT signaling pathway in regulating neuronal apoptosis. This study contributes to the ongoing exploration of molecular pathways involved in spinal cord injury (SCI) repair, focusing on the therapeutic potential of EPI-NCSC-CM. The research findings indicate that EPI-NCSC-CM exerts a neuroprotective effect by suppressing neuronal apoptosis through activation of the PI3K/AKT pathway in SCI rats. These results highlight the promising role of EPI-NCSC-CM as a potential treatment strategy for SCI, emphasizing the significance of the PI3K/AKT pathway in mediating its beneficial effects.

Project description:ObjectvesTransient receptor potential vanilloid 3 (TRPV3) is a member of the TRP channels family of Ca2+ -permeant cation channels. In this study, we aim to investigate the role of TRPV3 in pulmonary vascular remodeling and PASMCs proliferation under hypoxia.Materials and methodsThe expression of TRPV3 was evaluated in patients with pulmonary arterial hypertension (PAH) and hypoxic rats, using hematoxylin and eosin (H&E) and immunohistochemistry. In vitro, MTT assay, flow cytometry, Western blotting and immunofluorescence were performed to investigate the effects of TRPV3 on proliferation of PASMCs.ResultsWe found that, in vivo, the expression of TRPV3 was increased in patients with PAH and hypoxic rats. Right ventricular hypertrophy measurements and pulmonary pathomorphology data show that the ratio of the heart weight/tibia length (HW/TL), the right ventricle/left ventricle plus septum (RV/LV+S) and the medial width of the pulmonary artery were increased in chronic hypoxic rats. Moreover, the expression of proliferating cell nuclear antigen (PCNA), Cyclin D, Cyclin E and Cyclin A, phospho-CaMKII (p-CaMKII) were induced by hypoxia. In vitro, we revealed that hypoxia promoted PASMCs viability, increased the expression of PCNA, Cyclin D, Cyclin E, Cyclin A p-CaMKII, made more cells from G0 /G1 phase to G2 /M + S phase, enhanced the microtubule formation, and increased [Ca2+ ]i , which could be suppressed by Ruthenium Red, an inhibitor of TRPV3, and TRPV3 silencing has similar effects. Furthermore, the up-regulated expression of PCNA, Cyclin D, Cyclin E and Cyclin A, the increased number of cells in G2 /M and S phase, and the enhanced activation and expression of PI3K and AKT proteins induced by hypoxia and in presence of carvacrol (an agonist of TRPV3), was significantly attenuated by incubation of LY 294002, a specific inhibitor for PI3K/AKT.ConclusionsThese findings suggest that TRPV3 is involved in hypoxia-induced pulmonary vascular remodeling and promotes proliferation of PASMCs and the effect is, at least in part, mediated via the PI3K/AKT pathway.

Dataset Information

Conditioned medium from M2b macrophages modulates the proliferation, migration, and apoptosis of pulmonary artery smooth muscle cells by deregulating the PI3K/Akt/FoxO3a pathway.

Publications

Conditioned medium from M2b macrophages modulates the proliferation, migration, and apoptosis of pulmonary artery smooth muscle cells by deregulating the PI3K/Akt/FoxO3a pathway.

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