AUTHOR=Qin Chaoyi , Zan Yiheng , Xie Liang , Liu Hanmin 

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

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.942251

DOI=10.3389/fcvm.2022.942251

ISSN=2297-055X

ABSTRACT=<sec><title>Objective</title><p>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.</p></sec><sec><title>Methods</title><p>Primary cultures of PASMCs were treated with different concentrations of PDGF-BB or exogenous hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>). 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 H<sub>2</sub>O<sub>2</sub> were detected under the stimulation of different levels of PDGF-BB by Western blot and dihydroethidium staining.</p></sec><sec><title>Results</title><p>Both the control group and 50 ng/ml of the PDGF-BB group showed significantly higher levels of phosphorylation ATM compared to other groups (<italic>P</italic> &lt; 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 (<italic>P</italic> &lt; 0.05). Both the levels of NOX2 and H<sub>2</sub>O<sub>2</sub> showed dose-dependent manners under PDGF-BB stimulation (<italic>P</italic> &lt; 0.05). ATM could be activated by H<sub>2</sub>O<sub>2</sub> upon a dose-dependent way, except for the 500 μM H<sub>2</sub>O<sub>2</sub> group. Under 200 μM H<sub>2</sub>O<sub>2</sub> stimulation, proliferation level decreased significantly (<italic>P</italic> &lt; 0.05), while no significant difference was shown with the addition of ATM inhibitor (<italic>P</italic> &gt; 0.05).</p></sec><sec><title>Conclusion</title><p>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 H<sub>2</sub>O<sub>2</sub>. Our study might provide a novel promising target for the treatment of pulmonary arterial hypertension (PAH).</p></sec>