Investigating Novel Caveolar Protein Interactions in Cardiovascular Redox Signalling
- Publication Type:
- Thesis
- Issue Date:
- 2021
Open Access
Copyright Clearance Process
- Recently Added
- In Progress
- Open Access
This item is open access.
Cardiovascular disease (CVD) is a chronic disorder developing perniciously during the lifetime and usually progressing to an advanced stage by the time symptoms occur. CVD has been listed as the most common non-communicable disease globally. Notwithstanding some decline, CVD remains the principal cause of death in both developing and developed countries. Despite some recent success, current therapeutic methods are not efficient enough to prevent CVD, so it is essential to look for a novel therapeutic approach to preclude mortality and morbidity caused by CVD. FXYD1 protein is abundant in the heart tissue and is known to have a role in protecting cardiac sodium-potassium ATPase from oxidative stress. Nevertheless, little is known about the interaction of FXYD1, which is localised in caveolae, with other caveolae resident proteins in the heart, or the role of the FXYD1 in other cardiovascular tissues.
Endothelial function is predominately based on endothelial nitric oxide synthase (eNOS) function and activity. Oxidative stress activates the endothelial dysfunction, and it is a hall-mark of CVD. It has been demonstrated that FXYD1 protein protects eNOS from dysregulated redox signalling in the vasculature, making it a potential therapeutic target for vascular diseases.
To investigate the role and function of FXYD1 in cardiac and vascular redox signalling, the FXYD1 knock out mice, which exhibit enhanced oxidative stress and are prone to subtle increased cardiac dysfunction under normal conditions, were used in several models of cardiovascular disease, including atherosclerosis, diabetes, and hypertension. In addition, electron microscopy and proteomics techniques were applied to study the impact of FXYD1 on the morphology and protein contents of the caveolae. The caveolae and associated proteins were extracted using discontinuous sucrose gradient ultracentrifuge, and the expression level of redox enzymes and other protein of interests were determined by immunoblotting.
This thesis's overall findings are that FXYD1 appears to be protective against damage caused by oxidative stress and proinflammatory mediators. Overall, cardiovascular disease's effect appears to be balanced with no change in atherosclerosis plaque development or stability, whether FXYD1 was present or absent. Some of the changes, such as level of circulating IL-1ß and weight gain, in atherosclerotic mice were sex-dependent. Future studies may investigate targeting FXYD1 in specific sub-cellular regions such as the caveolae, which are redox hotspots, to lower oxidative stress without causing inflammation.
Please use this identifier to cite or link to this item: