Date of Award

5-2024

Document Type

Thesis

Degree Name

Master of Science (MS)

Program

Biomedical Science

Track

Molecular and Translational Physiology

Research Advisor

Djamel Lebeche PhD

Committee

Djamel Lebeche, PhD; Fan Zheng, PhD; Malik Kafait, Ph.D

Keywords

Diabetic Cardiomyopathy; Diabetes mellitus; MicroRNA; Multiplicity of Infection;SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a)

Abstract

Diabetes mellitus, one of the world’s fast-growing diseases, is characterized by high death rates from cardiac complications named diabetic cardiomyopathy (DCM). DCM is a heart disease that occurs in both type 1 and 2 diabetes mellitus patients. Many management options have been explored in the management of DCM, including ACE inhibitors, beta-blockers, etc.; however, limited success has been recorded from these. MicroRNAs, recently discovered gene regulators, have been reported to be associated with various physiology and pathological processes in the mammalian body. These include cell proliferation, cell death, senesis, carcinogenesis, diabetes, and heart failure, among others. Various miRs have been associated with heart disease, including heart failure; however, the impact of miRs in diabetes cardiomyopathy is unknown. Here, the microRNA microarray profile of diabetic mouse hearts revealed 15 overexpressed and 3 downregulated miR, of which miR-152 had the most significant fold change compared with the control. MiR-152 was also upregulated in the human diabetic heart by greater than 2-fold. Ad. miR-152 was constructed and transfected at MOI 5-10 into neonatal cardiomyocytes to overexpress miR-152 and assess its effect on cardiac myocytes and the pathogenesis of DCM. Bioinformatics and a proteomic approach were also used to identify miR-152 target genes. MiR-152 OE was seen to induce cardiac hypertrophy and increase protein synthesis in NCM. Calcium regulation, cardiac contractility, Glucose transport and metabolism, insulin signalling, and fatty acid oxidation pathway-associated genes were identified by bioinformatics and proteomics to be targeted by miR-152. Subsequently, results show SERCA2a, contractile function, AMPK expression and phosphorylation, ACC phosphorylation, glucose uptake, and AKT phosphorylation were significantly reduced in miR-overexpressed cardiomyocytes with or without insulin stimulation when compared to control, indicating dysfunction in calcium homeostasis, contractility, fatty acid oxidation, insulin signalling and glucose metabolism. These data confirm the involvement of miR-152 in the pathogenesis of diabetic cardiomyopathy, unraveling a novel therapeutic pathway in the management of DCM. To establish these pathways, miR-152 inhibition must be explored in vivo in animal models of DCM and human volunteers.

ORCID

https://orcid.org/0009-0001-7276-9682

DOI

10.21007/aetd.cghs.2024.0003

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Available for download on Saturday, November 22, 2025

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