DOI: 10.1161/jaha.125.047767 ISSN: 2047-9980

Pregnane X Receptor Activation Attenuates Aortic Dissection by Suppressing Lactate Dehydrogenase A–Mediated Lactate Metabolism

Lele Tang, Haoyu Li, Yukun Chen, Jiaqi Liu, Yong Lin, Debin Jiang, Yandan Chen, Guozhu Cheng, Xikai Guo, Yue Wang, Liangwan Chen, Ziwen Cai
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Background

The pathogenesis of thoracic aortic dissection (TAD) involves phenotypic switching of vascular smooth muscle cells (VSMCs) and VSMCs apoptosis. PXR (pregnane X receptor) is a known regulator of apoptosis. The mechanistic role of PXR in the pathogenesis of TAD remains elusive.

Methods

Microarray data sets related to TAD were obtained from the Gene Expression Omnibus database to identify differentially expressed genes. Four‐week‐old male Pxr ‐overexpressing mice, beta carotene–treated mice, and Ldha ‐knockdown mice were administered β‐aminopropionitrile (1 g/kg per day) in drinking water for 4 weeks, followed by intraperitoneal injection of angiotensin II (1.44 mg/kg 3 times daily) for 3 days to induce TAD. Lactate concentration and lactate dehydrogenase activity were measured using commercially available assay kits. Apoptosis was assessed by TUNEL staining. VSMC phenotype transformation was detected by quantitative real‐time polymerase chain reaction, immunofluorescence, and western blot.

Results

Microarray analysis of data sets from the Gene Expression Omnibus revealed downregulated PXR expression in aortic tissues from TAD patients. Consistently, reduced PXR expression was observed in aortic tissues from both TAD patients and β‐aminopropionitrile–induced TAD mice. β‐Aminopropionitrile–induced TAD progression was significantly ameliorated in mice with PXR overexpression or activation. PXR activation effectively suppressed VSMCs phenotypic switching. It also inhibited LDHA expression, thereby reducing lactate accumulation, attenuating VSMC apoptosis, and ultimately alleviating TAD progression. In line with these findings, β‐aminopropionitrile–induced TAD progression was significantly ameliorated in Ldha ‐knockdown mice.

Conclusions

PXR signaling may represent a novel target for the prevention and treatment of TAD.

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