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Sitagliptin Protects Cardiac Function by Reducing Nitroxidative Stress and Promoting Autophagy in Zucker Diabetic Fatty (ZDF) Rats

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Abstract

Purpose

The purpose of the study is to identify potential mechanisms involved in the cardiac protective effects of sitagliptin in Zucker diabetic fatty (ZDF) rats.

Methods and Results

Male non-diabetic lean Zucker rats (Lean) and ZDF rats treated with saline (ZDF) or sitagliptin (ZDF + sita) were used in this study. The blood pressure and lipid profiles were increased significantly in ZDF rats compared with Lean rats. ZDF + sitagliptin rats had decreased systolic blood pressure compared with ZDF rats. Sitagliptin treatment decreased total cholesterol (TC), triglycerides (TGs), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels. Ejection fraction (EF) and fractional shortening (FS) were decreased in ZDF rats, which improved with sitagliptin from 59.8% ± 3.0 and 34.5% ± 3.1 to 66.9% ± 3.4 and 40.9% ± 4.2, respectively. Moreover, the nitroxidative stress level was increased while autophagy levels were decreased in ZDF rats, which was reversed by the administration of sitagliptin. Treatment with sitagliptin or FeTMPyP improved the autophagy level in high-glucose cultured H9c2 cells by increasing autolysosome numbers from 15 ± 4 to 21 ± 3 and 22 ± 3, respectively. We detected a positive correlation between DPP-4 activity and 3-nitrotyrosine levels (r = 0.3903; P < 0.01), a negative correlation between Beclin-1 levels and DPP-4 activity (r = − 0.3335; P < 0.01), and a negative correlation between 3-nitrotyrosine and Beclin-1 levels (r = − 0.3794; P < 0.01) in coronary heart disease patients.

Conclusions

Sitagliptin alleviates diabetes-induced cardiac injury by reducing nitroxidative stress and promoting autophagy. This study indicates a novel target pathway for the treatment of cardiovascular complications in type 2 diabetes mellitus.

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Acknowledgments

We appreciate Mrs. Qing Xu for the help with Doppler ultrasound for cardiac function detection in the Core Facility Center, Capital Medical University (Bei**g, China). We also thank Dr. Qian Fan and Ms. **aochun Yang for collecting the serum samples of CHD patients in Beijng Anzhen Hospital.

This work was funded by the Natural Science Foundation of Bei**g (no. 7151001) and Scientific Research Foundation of Bei**g Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases (no. 2015DXWL03). We thank Edanz Group China (www.liwenbianji.cn/ac) for editing the English text of this manuscript.

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Authors and Affiliations

  1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, No. 10 **toutiao, You An Men, Fengtai District, Bei**g, 100069, China

    Yi Zhou, Huanyuan Wang, Jiahui Xu, Wen**g Yan, Jiaying Li & Wen Wang

  2. Department of Endocrine, Bei**g Hospital, National Center of Gerontology, No. 1 Dahua Road, Dong Dan, Dongcheng District, Bei**g, 100730, China

    Fuli Man & Qi Pan

  3. Department of Pathophysiology, School of Basic Medicine, **ing Medical University, **ing, 272067, Shandong, China

    Zhiying Guo

  4. Bei**g Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Bei**g, 100069, China

    Zhiying Guo & Wen Wang

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  1. Yi Zhou
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Contributions

Wen Wang, Qi Pan, Zhiying Guo, and Yi Zhou contributed to the conception and design of the study. Yi Zhou drafted the article. Yi Zhou, Huanyuan Wang, Zhiying Guo, and Jiahui Xu performed the experiments, data acquisition, and data analysis. Fuli Man, Wen**g Yan, Jiahui Xu, and Jiaying Li critically revised the article, gave final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy.

Corresponding authors

Correspondence to Qi Pan or Wen Wang.

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Conflict of Interest

The authors declare that they have no conflict of interest.

Research Involving Animals

All procedures performed in studies involving animals were in accordance with the “Guiding Principles in the Use and Care of Animals” published by the National Institutes of Health (NIH Publication No. 85-23, Revised 1996) and approved by the Institutional Animal Care and Use Committee of Capital Medical University.

Research Involving Human Participants

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All subjects have been informed of the purpose and nature of this study and given written informed consents. The study was approved by the local research ethics committee (Bei**g Anzhen Hospital, Capital Medical University, Bei**g, China).

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Zhou, Y., Wang, H., Man, F. et al. Sitagliptin Protects Cardiac Function by Reducing Nitroxidative Stress and Promoting Autophagy in Zucker Diabetic Fatty (ZDF) Rats. Cardiovasc Drugs Ther 32, 541–552 (2018). https://doi.org/10.1007/s10557-018-6831-9

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