Does activation of pregnane-X-receptor (PXR) prevent abdominal aortic aneurysm formation in preclinical models?
Activation of the nuclear receptor PXR protects against abdominal aortic aneurysm development by inhibiting oxidative stress, suggesting a potential novel therapeutic target.
Abdominal aortic aneurysm (AAA) is a life-threatening condition, but effective medications to prevent its progression and rupture are currently lacking. The nuclear receptor pregnane-X-receptor (PXR) plays a crucial role in vascular homeostasis. However, the role of PXR in AAA development remains unknown. We first detected the PXR expression in human and murine AAA tissues by RT-qPCR and Western blot. To investigate the potential role of PXR in the development of AAA, we used adeno-associated virus-mediated overexpression of PXR and pharmacological activation of PXR by ginkgolide A (GA) in mouse AAA models induced by both angiotensin II (AngII) and calcium phosphate Ca 3 (PO 4 ) 2 . The underlying mechanism was further explored using RNA-sequencing and molecular biological analyses. We found a significant decrease in both mRNA and protein levels of PXR in both human and murine aortic smooth muscle cells from AAA tissues, accompanied with phenotypic switching of vascular smooth muscle cell and increased oxidative stress. PXR overexpression in abdominal aortas and GA treatment successfully suppressed AAA formation in both mouse AAA models. RNA-sequencing data revealed that PXR activation inhibited gamma-aminobutyric acid type A receptor subunit alpha3 (GABRA3) expression. Additional mechanistic studies identified that PXR suppressed AAA through mitigating GABRA3-induced reactive oxygen species (ROS) generation and subsequent phosphorylation of c-Jun N-terminal kinase (JNK). Interestingly, p-JNK was found to induce ubiquitin-proteasome degradation of PXR. In summary, our data unveiled, for the first time, the protective role of PXR against AAA pathogenesis by inhibiting oxidative stress. These findings suggested PXR as a promising therapeutic target for AAA. • PXR is down-regulated in human and murine AAA tissues. • Overexpression or pharmacological activation of PXR represses AAA formation. • PXR suppresses AAA through inhibiting GABRA3-mediated ROS generation. • Oxidative stress-activated JNK upregulates pathological processes of AAA. • P-JNK induces the ubiquitin-proteasome degradation of PXR.
Shen et al. (Thu,) studied this question.