DRD4 (Dopamine D4 Receptor) Mitigate Abdominal Aortic Aneurysm via Decreasing P38 MAPK (mitogen-activated protein kinase)/NOX4 (NADPH Oxidase 4) Axis–Associated Oxidative Stress

Abstract

Oxidative stress plays a vital role in the development of abdominal aortic aneurysm (AAA). DRD4 (dopamine D4 receptor) is involved in oxidative stress. Here, we reasoned that DRD4 may mitigate AAA by its antioxidative effect. Currently, in vivo, DRD4 expression was reduced in AAA patients and experimental models determined by quantitative polymerase chain reaction and Western blot. Reactive oxygen species (ROS) was increased in elastase perfused aorta from Drd4 −/− mice compared with elastase perfused wild-type ( WT ) aorta determined by dihydroethidium staining and malondialdehyde, accompanying with more apoptotic vascular smooth muscle cells, inflammatory infiltration, and ECM (extracellular matrix) degradation determined by terminal deoxynucleotidyl transferase-mediated nick end labeling assay, immunohistochemistry, Van Gieson staining, and zymography, respectively. However, pharmacological activation of DRD4 reduced the ROS production and mitigated pathological characteristics of AAA. In vitro, activated DRD4 alleviated ROS production and apoptosis determined by 2,7-dichlorodihydrofluorescein diacetate, dihydroethidium, malondialdehyde, and flow cytometry, whereas DRD4 deficiency or inhibited DRD4 exerted the opposite effect in vascular smooth muscle cells. In terms of mechanism, in vivo, DRD4 deficiency upregulated NOX4 (NADPH oxidase 4) expression instead of other subunits, meanwhile, phosphorylated P38 mitogen-activated protein kinase was also augmented instead of other mitogen-activated protein kinase pathways. In vitro, pharmacological activation of DRD4 downregulated phosphorylated P38 and NOX4 in vascular smooth muscle cells, vice versa. Interestingly, DRD4 mediated the expression of NOX4 through a P38 mitogen-activated protein kinase pathway–dependent manner, which regulated ROS production. DRD4 mitigated AAA progression by downregulating P38 mitogen-activated protein kinase/NOX4 axis mediated ROS production in vascular smooth muscle cells. Therefore, DRD4 may serve as a novel therapeutic target for AAA treatment.