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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Supervisor

Singh, Krishna

Abstract

Heart-type fatty acid binding protein (FABP3) is an effective biomarker for cardiac injuries. However, it has also been tested as a biomarker in patients with peripheral artery diseases; these conditions are complications of atherosclerosis, which is driven by endothelial dysfunction. As FABP3 release is not exclusive to the heart but appears to characterize cardiovascular events, whether FABP3 influences endothelial function is not known. Additionally, the transcriptomic profiles of endothelial cells during cardiovascular stresses remain under-investigated. This thesis investigates the multifaceted role of FABP3 and the transcriptomic alterations in endothelial cells under different cardiovascular stressors, offering novel insights into endothelial dysfunction and atherosclerosis. Through a series of in vitro studies, the regulatory dynamics of FABP3 under atherosclerotic stressors, its impact on endothelial cell gene expression, and the effects of Angiotensin II (Ang II) exposure on coding and long noncoding RNAs were demonstrated. The findings of this thesis reveal that FABP3 expression is differentially modulated by oxidative stress, inflammation, and hypertension and highlight its therapeutic potential in cardiovascular diseases through loss of function studies. Additionally, transcriptomic profiling uncovers significant changes in messenger RNAs and long non-coding RNAs, identifying novel pathways involved in endothelial response to Ang II-induced stress. This comprehensive analysis advances the understanding of the molecular mechanisms underlying endothelial dysfunction and opens new avenues for research on intervention in endothelial dysfunction, atherosclerosis, and cardiovascular disease.

Summary for Lay Audience

This thesis examines the protein Heart-type Fatty Acid Binding Protein 3 (FABP3) and the associated genetic changes in the cells lining blood vessels under the context of diseases involving blood vessels. The work addresses our previous observation that FABP3 rises in blood were not exclusive to patients with heart injury, as they were also detected in patients with only vessel disease. We showed that FABP3 in the cells lining the blood vessels reacts uniquely under conditions that lead to heart and vascular diseases, including inflammation, oxidative stress, and lack of oxygen, revealing its treatment potential. Exposure to a hormone associated with high blood pressure, angiotensin II, also alters the genetics of blood vessel linings, including those genes that do not produce proteins but regulate others, which have implications for blood vessel responses to stress. The thesis further identifies new biological pathways activated in stressed conditions by analyzing the entire set of genetic material in the cells of blood vessel linings, opening up new avenues for combating heart and blood vessel diseases. In essence, this study advances the understanding of heart and vessel diseases at the molecular level, suggesting new strategies for prevention and treatment.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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