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Glycosphingolipids promote pro-atherogenic pathways in the pathogenesis of hyperglycemia-induced accelerated atherosclerosis

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Abstract

Introduction

Three out of four people with diabetes will die of cardiovascular disease. However, the molecular mechanisms by which hyperglycemia promotes atherosclerosis, the major underlying cause of cardiovascular disease, are not clear.

Objectives

Three distinct models of hyperglycemia-associated accelerated atherosclerosis were used to identify commonly altered metabolites and pathways associated with the disease.

Methods

Normoglycemic apolipoprotein-E-deficient mice served as atherosclerotic control. Hyperglycemia was induced by multiple low-dose streptozotocin injections, or by introducing a point-mutation in one copy of insulin-2 gene. Glucosamine-supplemented mice, which experience accelerated atherosclerosis to a similar extent as hyperglycemia-induced models without alterations in glucose or insulin levels, were also included in the analysis. Untargeted plasma metabolomics were used to investigate hyperglycemia-associated accelerated atherosclerosis in three disease models. The effect of specific significantly altered metabolites on pro-atherogenic processes was investigated in cultured human vascular cells.

Results

Hyperglycemic and glucosamine-supplemented mice showed distinct metabolomic profiles compared to controls. Meta-analysis of three disease models revealed 62 similarly altered metabolite features (FDR-adjusted p < 0.05). Identification of shared metabolites revealed alterations in glycerophospholipid and sphingolipid metabolism, and pro-atherogenic processes including inflammation and oxidative stress. Post-multivariate and pathway analyses indicated that the glycosphingolipid pathway is strongly associated with hyperglycemia-induced accelerated atherosclerosis in these atherogenic mouse models. Glycosphingolipids induced oxidative stress and inflammation in cultured human vascular cells.

Conclusion

Glycosphingolipids are strongly associated with hyperglycemia-induced accelerated atherosclerosis in three distinct models. They also promote pro-atherogenic processes in cultured human cells. These results suggest glycosphingolipid pathway may be a potential therapeutic target to block or slow atherogenesis in diabetic patients.

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Acknowledgements

The authors would like to thank Dr. Peter Shi for providing the human cell lines for the in vitro experiments and the Centre for Microbial Chemical Biology at McMaster University for access to the Mass Spectrometer. This research was supported by operating grants from the Canadian Institutes of Health Research (MOP62910 and MOP142248) and the Heart and Stroke Foundation of Canada (G-17-0017029). V.T.D. is supported by an International Ontario Graduate Scholarship.

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Authors and Affiliations

  1. Thrombosis and Atherosclerosis Research Institute, McMaster University, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada

    Vi T. Dang, Lexy H. Zhong, Aric Huang, Arlinda Deng & Geoff H. Werstuck

  2. Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada

    Vi T. Dang, Aric Huang & Geoff H. Werstuck

  3. Department of Medicine, McMaster University, Hamilton, ON, Canada

    Geoff H. Werstuck

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  1. Vi T. Dang
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  2. Lexy H. Zhong
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  3. Aric Huang
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  4. Arlinda Deng
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  5. Geoff H. Werstuck
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Contributions

GHW and VTD conceived and designed the study. VTD and AH performed mouse experiments. VTD, LHZ and AD conducted and analyzed histochemistry and in vitro experiments. VTD performed all metabolomic experiments and analyses. All authors reviewed and approved the final version of the manuscript.

Corresponding author

Correspondence to Geoff H. Werstuck.

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Conflict of interest

Vi Dang, Lexy Zhong, Aric Huang, Arlinda Deng and Geoff Werstuck declare no conflict of interest.

Ethical approval

All animal procedures were pre-approved by, and performed in accordance with, the McMaster University Animal Research Ethics Board and conform with the guidelines of the Canadian Council on Animal Care.

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Dang, V.T., Zhong, L.H., Huang, A. et al. Glycosphingolipids promote pro-atherogenic pathways in the pathogenesis of hyperglycemia-induced accelerated atherosclerosis. Metabolomics 14, 92 (2018). https://doi.org/10.1007/s11306-018-1392-2

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