2. Academic Validation
  3. 1,25-Dihydroxyvitamin D attenuates diabetic cardiac autophagy and damage by vitamin D receptor-mediated suppression of FoxO1 translocation

1,25-Dihydroxyvitamin D attenuates diabetic cardiac autophagy and damage by vitamin D receptor-mediated suppression of FoxO1 translocation

  • J Nutr Biochem. 2020 Jun;80:108380. doi: 10.1016/j.jnutbio.2020.108380.
Xiaoping Guo 1,  Hongkun Lin 1,  Jingjing Liu 1,  Dongxia Wang 1,  Dan Li 1,  Chunjie Jiang 1,  Yuhan Tang 1,  Jun Wang 2,  Tingrui Zhang 3,  Yanyan Li 4,  Ping Yao 5
Affiliations

Affiliations

  • 1 Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 2 Shenzhen Center for Chronic Disease Control, 2021 Buxin Road, Shenzhen 518020, PR China.
  • 3 Department of Nutrition and Food Hygiene, School of Health Sciences, Wuhan University, 115 DongHu Road, Wu Chang District, Wuhan City 430072, China.
  • 4 Shenzhen Center for Chronic Disease Control, 2021 Buxin Road, Shenzhen 518020, PR China. Electronic address: lyyhust@126.com.
  • 5 Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Ministry of Education Key Laboratory of Environment, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: yaoping@mails.tjmu.edu.cn.
PMID: 32299030 DOI: 10.1016/j.jnutbio.2020.108380
Abstract

Cardiovascular abnormalities are one of the most important complications associated with diabetes. However, the effect of 1, 25-dihydroxyvitamin D (1,25D) on the diabetic heart and the associated regulatory mechanisms are not well appreciated. Here, we report that activation of the vitamin D receptor (VDR) by 1,25D depresses autophagic activity by inhibiting nuclear FoxO1 translocation to attenuate diabetic heart damage. Treatment with 1,25D improved oral glucose tolerance test outcomes, fasting blood glucose levels and CK-MB release in Zucker diabetic fatty (ZDF, fa/fa) rats. Moreover, 1,25D intervention decreased the expression of Bcl-2, Bax, cleaved Caspase-3, nuclear FoxO1, LC3II/LC3I and Beclin1 in the hearts of ZDF rats. However, VDR was noticeably up-regulated by 1,25D, which was inhibited in diabetic hearts. In the cardiomyocyte cell line H9c2, further accumulation of LC3II and the augmentation of p62 after treatment with high glucose and chloroquine confirmed increased autophagic activity in diabetic hearts. Moreover, increased Bcl-2 and Bax levels were observed after treatment with an agonist (rapamycin) and antagonist (3MA) of Autophagy in high-glucose-cultured cells. The knockdown of VDR with siRNA further induced the expression of LC3II and FoxO1 translocation and altered the Bax/Bcl-2 ratio in high-glucose-exposed cells, and these effects were suppressed by treatment with 1,25D or an inhibitor of FoxO1 transcriptional activity. In summary, 1,25D supplementation attenuated diabetic heart-related cardiac Autophagy and damage by activating the VDR to inhibit the nuclear translocation of FoxO1.

Keywords

Apoptosis; Autophagy; Diabetic heart damage; Forkhead box protein O1 translocation; Vitamin D receptor.

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