Ataxia telangiectasia mutated: The potential negative regulator in platelet-derived growth factor-BB promoted proliferation of pulmonary arterial smooth muscle cells

Chaoyi Qin; Yiheng Zan; Liang Xie; Hanmin Liu

doi:10.3389/fcvm.2022.942251

Ataxia telangiectasia mutated: The potential negative regulator in platelet-derived growth factor-BB promoted proliferation of pulmonary arterial smooth muscle cells

Front Cardiovasc Med. 2022 Aug 3:9:942251. doi: 10.3389/fcvm.2022.942251. eCollection 2022.

Authors

Chaoyi Qin¹, Yiheng Zan^{2

3

4}, Liang Xie^{2

3

4}, Hanmin Liu^{2

3

5}

Affiliations

¹ Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China.
² Pulmonary Vascular Remodeling Research Unit, West China Institute of Women's and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China.
³ Key Laboratory of Obstetric and Gynecologic and Pediatric Disease, Chengdu, China.
⁴ Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.
⁵ Department of Burns and Plastic Surgery, West China Hospital, Sichuan University, Chengdu, China.

Abstract

Objective: To study the role of ataxia telangiectasia mutated (ATM) in the platelet-derived growth factor (PDGF)-BB-induced proliferation of pulmonary arterial smooth muscle cells (PASMCs) through reactive oxygen species (ROS) formation.

Methods: Primary cultures of PASMCs were treated with different concentrations of PDGF-BB or exogenous hydrogen peroxide (H₂O₂). The activation level of ATM and the proliferation level of PASMCs were measured by immunofluorescence staining and Cell Counting Kit-8, respectively. Moreover, NADPH oxidase 2 (NOX2) and intracellular H₂O₂ were detected under the stimulation of different levels of PDGF-BB by Western blot and dihydroethidium staining.

Results: Both the control group and 50 ng/ml of the PDGF-BB group showed significantly higher levels of phosphorylation ATM compared to other groups (P < 0.05). With the ATM inhibitor, 50 ng/ml of the PDGF-BB group showed further increased proliferative level compared to the 10 ng/ml (P < 0.05). Both the levels of NOX2 and H₂O₂ showed dose-dependent manners under PDGF-BB stimulation (P < 0.05). ATM could be activated by H₂O₂ upon a dose-dependent way, except for the 500 μM H₂O₂ group. Under 200 μM H₂O₂ stimulation, proliferation level decreased significantly (P < 0.05), while no significant difference was shown with the addition of ATM inhibitor (P > 0.05).

Conclusion: Our study first established ROS-induced ATM activation in PDGF-BB-stimulated proliferation of PASMCs. Inhibition of ATM had promoted effects on the proliferation of PASMCs under the excessive levels of PDGF-BB and H₂O₂. Our study might provide a novel promising target for the treatment of pulmonary arterial hypertension (PAH).

Keywords: ROS; ataxia telangiectasia mutated; proliferation; pulmonary arterial hypertension; smooth muscle cell.