p-Cresyl sulfate promotes the formation of atherosclerotic lesions and induces plaque instability by targeting vascular smooth muscle cells

Abstract

Coronary atherosclerosis is a major complication of chronic kidney disease. This condition contributes to the increased mortality in dialysis patients. p-Cresyl sulfate (PCS) is a prototype of protein-bound uremic toxins that cannot be efficiently removed through routine dialysis procedures. In the present study, ApoE^−/− mice that underwent 5/6 nephrectomy were randomly divided into two groups, namely, vehicle-treated group (n = 20) and PCS-treated group (n = 20). Mice were sacrificed for en face and immunohistological analyses after 8 or 24 weeks of high-fat diet. Rat aortic vascular smooth muscle cells (VSMCs) were treated with phosphate buffer solution or 500 µmol/L PCS for in vitro evaluation. PCS-treated mice were observed to suffer increased atherosclerotic lesions after eight weeks of PCS administration. Moreover, 24 weeks of PCS administration also markedly increased the vulnerability index of aortic plaques. PCS was also observed to facilitate the migration and proliferation of VSMCs during the progression of the disease. Moreover, PCS disturbed the balance between matrix metalloproteinases and tissue inhibitor of metalloproteinases within the plaques. Thus, PCS played a vital role in promoting atherogenesis and disturbing the stability of formed plaques probably by targeting VSMCs.

Keywords

p-cresyl sulfate / atherosclerosis / plaque stability / vascular smooth muscle cell

References

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (Nos. 81370401, 81370397, 81570316, and 81500196).

Compliance with ethics guidelines

Hui Han, Yanjia Chen, Zhengbin Zhu, Xiuxiu Su, Jingwei Ni, Run Du, Ruiyan Zhang, and Wei Jin have no conflict of interest concerning this paper. All institutional and national guidelines for the care and use of laboratory animals were followed. This study was approved by the Committee on the Ethics of Animal Experiments of the Shanghai Jiao Tong University School of Medicine (Permit Number: [2012]-86), and was performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 2011).

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