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USP18 Curbs the Progression of Metabolic Hypertension by Suppressing JAK/STAT Pathway

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Abstract

Hypertension is a pathological state of the metabolic syndrome that increases the risk of cardiovascular disease. Managing hypertension is challenging, and we aimed to identify the pathogenic factors and discern therapeutic targets for metabolic hypertension (MHR). An MHR rat model was established with the combined treatment of a high-sugar, high-fat diet and ethanol. Histopathological observations were performed using hematoxylin–eosin and Sirius Red staining. Transcriptome sequencing was performed to screen differentially expressed genes. The role of ubiquitin-specific protease 18 (USP18) in the proliferation, apoptosis, and oxidative stress of HUVECs was explored using Cell Counting Kit-8, flow cytometry, and enzyme-linked immunosorbent assays. Moreover, USP18 downstream signaling pathways in MHR were screened, and the effects of USP18 on these signaling pathways were investigated by western blotting. In the MHR model, total cholesterol and low-density lipoprotein levels increased, while high-density lipoprotein levels decreased. Moreover, high vessel thickness and percentage of collagen were noted along with increased malondialdehyde, decreased superoxide dismutase and catalase levels. The staining results showed that the MHR model exhibited an irregular aortic intima and disordered smooth muscle cells. There were 78 differentially expressed genes in the MHR model, and seven hub genes, including USP18, were identified. USP18 overexpression facilitated proliferation and reduced apoptosis and oxidative stress in HUVECs treated with Ang in vitro. In addition, the JAK/STAT pathway was identified as a USP18 downstream signaling pathway, and USP18 overexpression inhibited the expression of JAK/STAT pathway-related proteins. Conclusively, USP18 restrained MHR progression by promoting cell proliferation, reversing apoptosis and oxidative stress, and suppressing the JAK/STAT pathway.

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Data Availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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  1. Zhihong Xie and Mingshan Huang are co-first authors.

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  1. Department of Cardiology, Ganzhou People’s Hospital, 16 Meiguan Dadao, Zhanggong District, Ganzhou, 341000, Jiangxi, China

    Zhihong Xie, Mingshan Huang, Wang Xu, Fuwei Liu & Donghua Huang

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Contributions

Zhihong Xie and Mingshan Huang: conception, design and analysis of data, performed the data analyses and wrote the manuscript; Wang Xu and Fuwei Liu: contributed to the conception of the study; wrote the manuscript; Donghua Huang: contributed significantly to analysis and manuscript preparation; wrote the manuscript; All authors have read and approved the manuscript.

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The experiments conformed to the Guide for the Care and Use of Laboratory Animals. Animal study has been approved by the Animal Ethics Committee of Ganzhou People’s Hospital (TY-DKY2023-009-01). All methods are reported in accordance with ARRIVE guidelines.

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Xie, Z., Huang, M., Xu, W. et al. USP18 Curbs the Progression of Metabolic Hypertension by Suppressing JAK/STAT Pathway. Cardiovasc Toxicol 24, 576–586 (2024). https://doi.org/10.1007/s12012-024-09860-7

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