2. Academic Validation
  3. Melatonin attenuates diabetic cardiomyopathy by increasing autophagy of cardiomyocytes via regulation of VEGF-B/GRP78/PERK signaling pathway

Melatonin attenuates diabetic cardiomyopathy by increasing autophagy of cardiomyocytes via regulation of VEGF-B/GRP78/PERK signaling pathway

  • Cardiovasc Diabetol. 2024 Jan 9;23(1):19. doi: 10.1186/s12933-023-02078-x.
Shengzheng Zhang 1,  Wencong Tian 2,  Xianxian Duan 1,  Qian Zhang 1,  Lei Cao 1 2,  Chunlei Liu 1,  Guangru Li 1,  Ziwei Wang 1,  Junwei Zhang 1,  Jing Li 1,  Liang Yang 1 2,  Yang Gao 1 2,  Yang Xu 1,  Jie Liu 1,  Jie Yan 1,  Jianlin Cui 1,  Lifeng Feng 1,  Chang Liu 3 4,  Yanna Shen 5 6,  Zhi Qi 7 8 9
Affiliations

Affiliations

  • 1 Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China.
  • 2 Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, 300000, China.
  • 3 School of Medical Technology, Tianjin Medical University, Tianjin, 300203, China.
  • 4 Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, 571199, China.
  • 5 School of Medical Technology, Tianjin Medical University, Tianjin, 300203, China. shenyanna@tmu.edu.cn.
  • 6 Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou, 571199, China. shenyanna@tmu.edu.cn.
  • 7 Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, 300071, China. qizhi@nankai.edu.cn.
  • 8 Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, 300000, China. qizhi@nankai.edu.cn.
  • 9 Xinjiang Production and Construction Corps Hospital, Xinjiang, 830092, China. qizhi@nankai.edu.cn.
PMID: 38195474 DOI: 10.1186/s12933-023-02078-x
Abstract

Aims: Diabetic cardiomyopathy (DCM) is a major cause of mortality in patients with diabetes, and the potential strategies for treating DCM are insufficient. Melatonin (Mel) has been shown to attenuate DCM, however, the underlying mechanism remains unclear. The role of vascular endothelial growth factor-B (VEGF-B) in DCM is little known. In present study, we aimed to investigate whether Mel alleviated DCM via regulation of VEGF-B and explored its underlying mechanisms.

Methods and results: We found that Mel significantly alleviated cardiac dysfunction and improved Autophagy of cardiomyocytes in type 1 diabetes mellitus (T1DM) induced cardiomyopathy mice. VEGF-B was highly expressed in DCM mice in comparison with normal mice, and its expression was markedly reduced after Mel treatment. Mel treatment diminished the interaction of VEGF-B and Glucose-regulated protein 78 (GRP78) and reduced the interaction of GRP78 and protein kinase RNA -like ER kinase (PERK). Furthermore, Mel increased phosphorylation of PERK and eIF2α, then up-regulated the expression of ATF4. VEGF-B-/- mice imitated the effect of Mel on wild type diabetic mice. Interestingly, injection with Recombinant adeno-associated virus serotype 9 (AAV9)-VEGF-B or administration of GSK2656157 (GSK), an inhibitor of phosphorylated PERK abolished the protective effect of Mel on DCM. Furthermore, rapamycin, an Autophagy agonist displayed similar effect with Mel treatment; while 3-Methyladenine (3-MA), an Autophagy Inhibitor neutralized the effect of Mel on high glucose-treated neonatal rat ventricular myocytes.

Conclusions: These results demonstrated that Mel attenuated DCM via increasing Autophagy of cardiomyocytes, and this cardio-protective effect of Mel was dependent on VEGF-B/GRP78/PERK signaling pathway.

Keywords

Autophagy; Diabetic cardiomyopathy; Endoplasmic reticulum stress; Melatonin; VEGF-B.

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