Dosunmu-Ogunbi, Atinuke Oyinkansola
(2021)
The Role of Superoxide Dismutase 2 in Modulating Sickle Cell Disease Pathology.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Sickle cell disease (SCD) is an inherited hemoglobinopathy resulting from a point mutation in the β-globin gene. This substitution leads to the polymerization of sickle hemoglobin (HbS) under deoxygenated conditions and sickling of red blood cells (RBCs). Sickled RBCs can block the microvasculature causing vaso-occlusions and hemolyze releasing free hemoglobin and heme into the intravascular space. These processes cause an increase in the production of reactive oxygen species (ROS). Despite there being an increase in ROS production, there is a decrease in the antioxidant defense system. Superoxide dismutase 2 (SOD2) is an enzymatic antioxidant found only within the mitochondria which functions to dismutate superoxide to hydrogen peroxide. Given the decrease in antioxidants in SCD and that SOD2 is a known regulator of vascular function, this thesis project sought to identify whether SOD2 could modify SCD pathology.
In aim 1, we identified that a common polymorphism of SOD2, SOD2 V16A, is strongly associated with clinical indicators of pulmonary hyper`tension in SCD patients. In human pulmonary arterial endothelial cells (HPAECs), we found that this polymorphism pathologically
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associates with complex IV of the respiratory chain leading to a decrease in complex activity and mitochondrial respiration. HPAECs transduced with SOD2 V16A also had increased ROS production which was exacerbated with inhibition of complex III of the respiratory chain. In aim 2, we found that SOD2 protein expression is decreased in the pulmonary endothelium of SCD patients. In addition to this, we discovered that SOD2 protein expression was decreased in whole lung tissue of transgenic sickle mice. Given its significant decrease in sickle conditions, we went on to further define the function of SOD2 in the pulmonary endothelium using human pulmonary microvascular endothelial cells (HPMVECs). In HPMVECs, SOD2 deficiency led to a disruption in barrier function as well as a decrease in migration and proliferation. We found that these reduced functions were linked to a reduction in adhesion stemming from dysregulation of fibronectin processing. Altogether, we are the first to thoroughly investigate the role of SOD2 within the endothelium, and our findings can aide in the development of new therapeutics in the treatment of SCD patients.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
17 December 2021 |
| Date Type: |
Publication |
| Defense Date: |
14 October 2021 |
| Approval Date: |
17 December 2021 |
| Submission Date: |
28 October 2021 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
131 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Pharmacology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
sod2, sickle, sod2 v16a, SCD, mitochondria |
| Date Deposited: |
17 Dec 2021 15:49 |
| Last Modified: |
17 Dec 2023 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/41889 |
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