Subcellular mass spectrometric detection unveils hyperglycemic memory in the diabetic heart
Abstract Background Intensive glycemic control is insufficient to reduce the risk of heart failure in patients with diabetes mellitus. While the hyperglycemic memory in the diabetic cardiomyopathy has been well documented, its underlying mechanisms are not fully understood. The present study tried t...
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| Format: | Article |
| Language: | English |
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Wiley
2024-11-01
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| Series: | Journal of Diabetes |
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| Online Access: | https://doi.org/10.1111/1753-0407.70033 |
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| author | Jiabing Zhan Yufei Zhou Yifan Chen Kunying Jin Zhaoyang Chen Chen Chen Huaping Li Dao Wen Wang |
| author_facet | Jiabing Zhan Yufei Zhou Yifan Chen Kunying Jin Zhaoyang Chen Chen Chen Huaping Li Dao Wen Wang |
| author_sort | Jiabing Zhan |
| collection | DOAJ |
| description | Abstract Background Intensive glycemic control is insufficient to reduce the risk of heart failure in patients with diabetes mellitus. While the hyperglycemic memory in the diabetic cardiomyopathy has been well documented, its underlying mechanisms are not fully understood. The present study tried to investigate whether the dysregulated proteins/biological pathways, which persistently altered in diabetic hearts during normoglycemia, participate in the hyperglycemic memory. Methods Hearts of streptozotocin‐induced diabetic mice, with or without intensive glycemic control using slow‐release insulin implants, were collected. Proteins from total heart samples and subcellular fractions were assessed by mass spectrometry, Western blotting, and KEGG pathway enrichment analysis. mRNA sequencing was used to determine whether the persistently altered proteins were regulated at the transcriptional or post‐transcriptional level. Results Western blot validation of several proteins with high pathophysiological importance, including MYH7, HMGCS2, PDK4, and BDH1, indicated that mass spectrometry was able to qualitatively, but not quantitatively, reflect the fold changes of certain proteins in diabetes. Pathway analysis revealed that the peroxisome, PPAR pathway, and fatty acid metabolism could be efficiently rescued by glycemic control. However, dysregulation of oxidative phosphorylation and reactive oxygen species persisted even after normalization of hyperglycemia. Notably, mRNA sequencing revealed that dysregulated proteins in the oxidative phosphorylation pathway were not accompanied by coordinated changes in mRNA levels, indicating post‐transcriptional regulation. Moreover, literature review and bioinformatics analysis suggested that hyperglycemia‐induced persistent alterations of miRNAs targeted genes from the persistently dysregulated oxidative phosphorylation pathway, whereas, oxidative phosphorylation dysfunction‐induced ROS regulated miRNA expression, which thereby might sustained the dysregulation of miRNAs. Conclusions Glycemic control cannot rescue hyperglycemia‐induced alterations of subcellular proteins in the diabetic heart, and persistently altered proteins are involved in multiple functional pathways, including oxidative phosphorylation. These findings might provide novel insights into hyperglycemic memory in diabetic cardiomyopathy. |
| format | Article |
| id | doaj-art-f621eab34c654cf0949575f76d0dc37c |
| institution | Kabale University |
| issn | 1753-0393 1753-0407 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes |
| spelling | doaj-art-f621eab34c654cf0949575f76d0dc37c2024-11-26T07:02:35ZengWileyJournal of Diabetes1753-03931753-04072024-11-011611n/an/a10.1111/1753-0407.70033Subcellular mass spectrometric detection unveils hyperglycemic memory in the diabetic heartJiabing Zhan0Yufei Zhou1Yifan Chen2Kunying Jin3Zhaoyang Chen4Chen Chen5Huaping Li6Dao Wen Wang7Division of Cardiology, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDivision of Cardiology, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDepartment of Cardiology, Fujian Medical Center for Cardiovascular Diseases, Fujian Institute of Coronary Heart Disease Fujian Medical University Union Hospital Fuzhou ChinaDivision of Cardiology, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDepartment of Cardiology, Fujian Medical Center for Cardiovascular Diseases, Fujian Institute of Coronary Heart Disease Fujian Medical University Union Hospital Fuzhou ChinaDivision of Cardiology, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDivision of Cardiology, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDivision of Cardiology, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaAbstract Background Intensive glycemic control is insufficient to reduce the risk of heart failure in patients with diabetes mellitus. While the hyperglycemic memory in the diabetic cardiomyopathy has been well documented, its underlying mechanisms are not fully understood. The present study tried to investigate whether the dysregulated proteins/biological pathways, which persistently altered in diabetic hearts during normoglycemia, participate in the hyperglycemic memory. Methods Hearts of streptozotocin‐induced diabetic mice, with or without intensive glycemic control using slow‐release insulin implants, were collected. Proteins from total heart samples and subcellular fractions were assessed by mass spectrometry, Western blotting, and KEGG pathway enrichment analysis. mRNA sequencing was used to determine whether the persistently altered proteins were regulated at the transcriptional or post‐transcriptional level. Results Western blot validation of several proteins with high pathophysiological importance, including MYH7, HMGCS2, PDK4, and BDH1, indicated that mass spectrometry was able to qualitatively, but not quantitatively, reflect the fold changes of certain proteins in diabetes. Pathway analysis revealed that the peroxisome, PPAR pathway, and fatty acid metabolism could be efficiently rescued by glycemic control. However, dysregulation of oxidative phosphorylation and reactive oxygen species persisted even after normalization of hyperglycemia. Notably, mRNA sequencing revealed that dysregulated proteins in the oxidative phosphorylation pathway were not accompanied by coordinated changes in mRNA levels, indicating post‐transcriptional regulation. Moreover, literature review and bioinformatics analysis suggested that hyperglycemia‐induced persistent alterations of miRNAs targeted genes from the persistently dysregulated oxidative phosphorylation pathway, whereas, oxidative phosphorylation dysfunction‐induced ROS regulated miRNA expression, which thereby might sustained the dysregulation of miRNAs. Conclusions Glycemic control cannot rescue hyperglycemia‐induced alterations of subcellular proteins in the diabetic heart, and persistently altered proteins are involved in multiple functional pathways, including oxidative phosphorylation. These findings might provide novel insights into hyperglycemic memory in diabetic cardiomyopathy.https://doi.org/10.1111/1753-0407.70033diabetic cardiomyopathyhyperglycemic memorymass spectrometrysubcellular |
| spellingShingle | Jiabing Zhan Yufei Zhou Yifan Chen Kunying Jin Zhaoyang Chen Chen Chen Huaping Li Dao Wen Wang Subcellular mass spectrometric detection unveils hyperglycemic memory in the diabetic heart Journal of Diabetes diabetic cardiomyopathy hyperglycemic memory mass spectrometry subcellular |
| title | Subcellular mass spectrometric detection unveils hyperglycemic memory in the diabetic heart |
| title_full | Subcellular mass spectrometric detection unveils hyperglycemic memory in the diabetic heart |
| title_fullStr | Subcellular mass spectrometric detection unveils hyperglycemic memory in the diabetic heart |
| title_full_unstemmed | Subcellular mass spectrometric detection unveils hyperglycemic memory in the diabetic heart |
| title_short | Subcellular mass spectrometric detection unveils hyperglycemic memory in the diabetic heart |
| title_sort | subcellular mass spectrometric detection unveils hyperglycemic memory in the diabetic heart |
| topic | diabetic cardiomyopathy hyperglycemic memory mass spectrometry subcellular |
| url | https://doi.org/10.1111/1753-0407.70033 |
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