Yi Zhou1, Huanyuan Wang1, Fuli Man2, Zhiying Guo3,4, Jiahui Xu1, Wenjing Yan1, Jiaying Li1, Qi Pan5, Wen Wang6,7. 1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Fengtai District, Beijing, 100069, China. 2. Department of Endocrine, Beijing Hospital, National Center of Gerontology, No. 1 Dahua Road, Dong Dan, Dongcheng District, Beijing, 100730, China. 3. Department of Pathophysiology, School of Basic Medicine, Jining Medical University, Jining, 272067, Shandong, China. 4. Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Beijing, 100069, China. 5. Department of Endocrine, Beijing Hospital, National Center of Gerontology, No. 1 Dahua Road, Dong Dan, Dongcheng District, Beijing, 100730, China. panqi621@126.com. 6. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, No. 10 Xitoutiao, You An Men, Fengtai District, Beijing, 100069, China. wangwen@ccmu.edu.com. 7. Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Beijing, 100069, China. wangwen@ccmu.edu.com.
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.
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 ZDFrats treated with saline (ZDF) or sitagliptin (ZDF + sita) were used in this study. The blood pressure and lipid profiles were increased significantly in ZDFrats compared with Lean rats. ZDF + sitagliptinrats had decreased systolic blood pressure compared with ZDFrats. 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 ZDFrats, 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 ZDFrats, 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 diseasepatients. 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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