Zinc supplementation prevents cardiomyocyte apoptosis and congenital heart defects in embryos of diabetic mice

• Published in: Free radical biology & medicine Vol. 53; no. 8; pp. 1595 - 1606
• Main Authors: Kumar, Srinivasan Dinesh, Vijaya, Murugaiyan, Samy, Ramar Perumal, Dheen, S. Thameem, Ren, Minqin, Watt, Frank, Kang, Y. James, Bay, Boon-Huat, Tay, Samuel Sam Wah
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.10.2012
• Subjects: abnormal development; Animals; Antioxidant; apoptosis; Apoptosis - drug effects; Blood Glucose - metabolism; Blotting, Western; calcium; Cardiac malformations; cardiomyocytes; cardiomyopathy; Cells, Cultured; diabetes; Diabetes Complications - etiology; Diabetes Complications - pathology; Diabetes Complications - prevention & control; Diabetes Mellitus, Experimental - physiopathology; dietary mineral supplements; Dietary Supplements; Embryo, Mammalian - cytology; Embryo, Mammalian - drug effects; Embryo, Mammalian - metabolism; Embryos; Female; gene expression; glucose; glutathione; Glutathione - genetics; Glutathione - metabolism; Heart; Heart Defects, Congenital - etiology; Heart Defects, Congenital - pathology; Heart Defects, Congenital - prevention & control; humans; Immunoenzyme Techniques; in vitro studies; in vivo studies; ions; lipid peroxidation; Lipid Peroxidation - drug effects; Maternal diabetes; messenger RNA; Metallothionein; Metallothionein - genetics; Metallothionein - metabolism; Mice; microscopy; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; nitric oxide; Nuclear Microscopy; Oxidative Stress; phosphorus; Rats; Reactive Oxygen Species - metabolism; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; superoxide anion; superoxide dismutase; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; therapeutics; Zinc; Zinc - administration & dosage; Heart; NO; Mn; Oxidative stress; MDA; P; Cu; Cardiac malformations; Zn; STZ; OFT; GSH; EC; Fe; GSSG; MT; SOD; TBARS; Antioxidant; Embryos; GPx; Zinc; Maternal diabetes; Se; ROS; Mg; Mice; Nuclear microscopy; Ca; Metallothionein; H9c2 cells
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2012.07.008

Oxidative stress induced by maternal diabetes plays an important role in the development of cardiac malformations. Zinc (Zn) supplementation of animals and humans has been shown to ameliorate oxidative stress induced by diabetic cardiomyopathy. However, the role of Zn in the prevention of oxidative stress induced by diabetic cardiac embryopathy remains unknown. We analyzed the preventive role of Zn in diabetic cardiac embryopathy by both in vivo and in vitro studies. In vivo study revealed a significant decrease in lipid peroxidation, superoxide ions, and oxidized glutathione and an increase in reduced glutathione, nitric oxide, and superoxide dismutase in the developing heart at embryonic days (E) 13.5 and 15.5 in the Zn-supplemented diabetic group when compared to the diabetic group. In addition, significantly down-regulated protein and mRNA expression of metallothionein (MT) in the developing heart of embryos from diabetic group was rescued by Zn supplement. Further, the nuclear microscopy results showed that trace elements such as phosphorus, calcium, and Zn levels were significantly increased (P<0.001), whereas the iron level was significantly decreased (P<0.05) in the developing heart of embryos from the Zn-supplemented diabetic group. In vitro study showed a significant increase in cellular apoptosis and the generation of reactive oxygen species (ROS) in H9c2 (rat embryonic cardiomyoblast) cells exposed to high glucose concentrations. Supplementation with Zn significantly decreased apoptosis and reduced the levels of ROS. In summary, oxidative stress induced by maternal diabetes could play a role in the development and progression of cardiac embryopathy, and Zn supplementation could be a potential therapy for diabetic cardiac embryopathy. ▪ ► Oxidative stress induced by maternal diabetes is associated with heart malformations. ► Zn supplement restores the antioxidant system in the heart of embryos from diabetic mice. ► MT up-regulation protects hearts of embryos from Zn-supplemented diabetic mice. ► Zn supplement alters some trace elements in the embryonic heart of diabetic mice. ► Zn may be beneficial in prevention of diabetes-induced cardiac malformations in embryos.