Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Pathology and Laboratory Medicine

Supervisor

Chakrabarti, Subrata

2nd Supervisor

Feng, Biao

Co-Supervisor

Abstract

Diabetic cardiomyopathy (DCM) is a chronic diabetic complication affecting the heart. It is a significant and independent contributor to heart failure and characterized by cardiac fibrosis and left ventricular hypertrophy. Endothelial cells are the first cells to be damaged by hyperglycemia, leading to epigenetic modifications and subsequent signaling and transcription derangements that lead to endothelial dysfunction and therefore cardiac fibrosis. The role of the two noncoding RNA microRNA-9-5p and circRNA_012164 are investigated using in vivo and in vitro models of hyperglycemia. CircRNA_012164 is upregulated in the hearts of diabetic mice and in cells exposed to high glucose. This results in an inhibition of miR-9 levels, which leads to increased expression of ACTA2, COL1A1, FN1 and FSP1, genes related to cardiac fibrosis. Knockdown of circRNA_012164 recovers miR-9 levels and protects against endothelial dysfunction and fibrosis. Establishment of the circRNA_012164/miR-9 regulatory axis sheds new light on the role of ncRNA in chronic diabetic complications.

Summary for Lay Audience

Diabetic cardiomyopathy (DCM) is a consequence of long-term diabetes that affects the heart. It can lead to heart failure and is characterized by heart muscle stiffening and remodeling of structures in the heart. The high blood sugar seen in diabetes harms endothelial cells, the type of cells lining blood vessels in the heart. This damage causes changes in how genes are switched ‘on’ or ‘off’, leading to irregular behaviour in the cells and leading to problems in the heart. One of the most prominent problems this results in is the accumulation of fibrous proteins which affect heart function and structure, these changes lead to DCM.

This project investigated the role of two RNA molecules, microRNA-9-5p and circRNA_012164, in DCM. Both live mice and cells were used. Previous research has found that microRNA-9 activity in the heart is reduced in diabetes and adding more microRNA-9 into cells, reduced genes that damage the heart. Our results show that circRNA_012164 becomes more active in diabetic hearts. This increased activity reduces the levels of microRNA-9. When circRNA_012164 levels rise and microRNA-9 levels drop, endothelial cells become more irregular, and the genes related to heart muscle problems get activated more. Once circRNA_012164 is reduced, genes related to heart muscle problems do not get more activated, even when blood sugar levels are high and microRNA-9 levels went back up. This shows that circRNA_012164 activation by high blood sugar is damaging to the heart, and reducing circRNA_012164 activity may protect the heart from developing DCM.

CircRNA_012164 is a new molecule that has never been studied before. This project has shed some light on how it, along with microRNA-9, can contribute to long-term problems in people with diabetes.

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

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