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The involvement of disrupted mitochondrial pathways in pulmonary arterial hypertension as a tuberculosis sequela in a South African cohort.
Thesis (MSc)--Stellenbosch University, 2023.
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| Format: | Thesis |
| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2023
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| _version_ | 1867614027925946368 |
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| access_status_str | Open Access |
| author | Payne, Carmen-Marie |
| author2 | Maarman, Gerald |
| author_browse | Maarman, Gerald Payne, Carmen-Marie |
| author_facet | Maarman, Gerald Payne, Carmen-Marie |
| author_sort | Payne, Carmen-Marie |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (MSc)--Stellenbosch University, 2023. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/128481 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:45:31.220Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2023 |
| publishDateRange | 2023 |
| publishDateSort | 2023 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/128481 The involvement of disrupted mitochondrial pathways in pulmonary arterial hypertension as a tuberculosis sequela in a South African cohort. Payne, Carmen-Marie Maarman, Gerald Windvogel, Shantal Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Division of Medical Physiology. Pulmonary hypertension Tuberculosis -- Complications Mitochondrial pathology UCTD Thesis (MSc)--Stellenbosch University, 2023. ENGLISH ABSTRACT: Background: Pulmonary arterial hypertension (PAH) is defined as a mean pulmonary arterial pressure > 20 mmHg using right heart catheterisation. It leads to right ventricular (RV) hypertrophy and failure, affecting approximately 384 000 - 440 000 adults. PAH potentially associates with tuberculosis (TB), which remains a burden to South Africa, while data on PAH as a TB sequela are scarce. Mitochondrial oxidative and antioxidant pathways may play a role in this association. This study, therefore, aimed to investigate the involvement of mitochondrial pathways in PAH as a TB sequela in a South African cohort. Methods: Serum was collected from TB patients which formed part of a larger study. Three populations included: population 1, who completed TB treatment more than one year prior, population 2, who received in-hospital treatment at the time of data collection and population 3, with one or more previous TB episodes. Spectrophotometric assays, including thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD) and catalase (CAT) were performed on patient serum, as well as ELISA assays, for hypoxia-inducible factor (HIF)-1α and metallothioneins (MTs). Spearman’s rank tests were performed to assess correlations between serum markers and clinical endpoints. Thereafter, populations were stratified according to disease status: PAH and non-PAH patients using echocardiographic data, and mild or moderate PAH risk. Peripheral blood mononuclear cells (PBMCs) were isolated and analysed using high-resolution respirometry to investigate mitochondrial bioenergetics of population 2. Results: Increased CAT activity (p<O.05) was observed in population I in comparison to population 2, while increased SOD activity (pcO.05) was observed in population 3 compared to population I. TBARS was increased in patients with mild PAH risk (p<O.05). SOD activity in population 3 showed a strong negative correlation to Ele' ratio, a marker for left ventricular filling pressure, TBARS in PAH patients showed a strong negative correlation to E,/e' ratio and SOD activity showed a moderate negative correlation to left atrial size. Mitochondrial complex-I, and 2 linked respiration was elevated in population 2 compared to healthy individuals (p<O.OOOI) while complex—4 activity and residual oxygen consumption were. Discussion and conclusion: Changes in SOD and CAT activities in populations I and 3 may be underpinned by changes in hydrogen peroxide pathways. TBARS, SOD, CAT and MTS are poor biomarkers of PAH in the context of TB. Undetected HIF- I a suggests that hypoxia may not be involved in this context. Mitochondrial respiratory data suggest that TB infection or medication causes PBMCs to shift oxygen consumption from ATP production towards proton leak. The low complex—4 linked respiration suggests that mitochondrial content/biogenesis is reduced. Lastly, the reduced residual oxygen consumption suggests that the stressed PBMCs, due to the severe TB or medication, are compensating by reducing the usage of oxygen on non-mitochondrial pathways. AFRIKAANSE OPSOMMING: Agtergrond: Pulmonale arteriële hipertensie (PAH) word gedefinieer as 'n gemiddelde pulmonale arteriële druk > 20 mmHg met regterhartkateterisasie. Dit lei tot regterventrikulêre (RV) hipertrofie en versaking, wat ongeveer 384 000 - 440 000 volwassenes affekteer. PAH kan moontlik met tuberkulose (TB) assosieer, wat 'n gesondheidsprobleem in Suid-Afrika is, maar data oor PAH as ‘n TB-nagevolg is skaars. Mitokondriale oksidatiewe en antioksidante paaie kan dalk ‘n rol speel hiermee. Hierdie studie het dus ten doel om die betrokkenheid van mitokondriale paaie by PAH as 'n TB-nagevolg in 'n Suid-Afrikaanse populasie te ondersoek. Metodes: Serum van TB-pasiënte wat deel gevorm het van 'n groter studie is ingesamel. Drie subpopulasies is gebruik: populasie 1 het TB-behandeling meer as een jaar tevore voltooi, populasie 2 het binne-hospitaal behandeling ontvang ten tyde van datainsameling en populasie 3 het een of meer as een vorige TB-episode gehad. Serum spektrofotometriese toetse, insluitend tiobarbituursuur-reaktiewe stowwe (TBARS), superoksieddismutase (SOD) en katalase (CAT) is op pasiëntserum uitgevoer, en in aparte eksperimente is ELISA toetse gedoen om hipoksieinduseerbare faktor (HIF)-1α en metallothioneïns (MT’s) te meet. Spearman se toetse tussen serum biomerkers en kliniese uitkomste is uitgevoer. Daarna is die subpopulasies ingedeel volgens siektestatus: PAH en nie-PAH, en lae PAH-risiko of matige PAH-risiko. Perifere bloed mononukliêre selle (PBMC's) is geïsoleer en geanaliseer met hoë resolusie respirometrie om mitokondriale bioenergetiese en metabolisme van subpopulasie 2 te ondersoek. Resultate: Verhoogde CAT aktiwiteit (p<0.05) is in populasie I waargeneem in vergelyking met populasie 2, terwyl verhoogde SOD aktiwiteit (p<0.05) in populasie 3 waargeneem is in vergelyking met populasie l. TBARS was verhoog in pasiénte met lae PAH-risiko SOD-aktiwiteit in populasie 3 het 'n sterk negatiewe korrelasie tot EJe'-verhouding getoon, 'n merker vir linkerventrikulére vullingsdruk, TBARS in PAH-pasiente het 'n sterk negatiewe korrelasie met E/e'-verhouding getoon en SOD-aktiwiteit het 'n matige negatiewe korrelasie met linker atriale grootte getoon. Mitokondriale kompleks-l en -2 gekoppelde respirasie was verhoog in populasie 2 in vergelyking met gesonde individue (11<0.0001) terwyl kompleks-4 aktiwiteit en residuele suurstofverbruik was aansieklik verminder. Bespreking en gevolgtrekking: Veranderinge wat in SOD- en CAT-aktiwiteite in populasies 1 en 3 gesien word, kan toegeskryf word aan veranderinge in waterstofperoksied paaie. TBARS, SOD, CAT en MT's is swak biomerkers van PAH in die konteks van TB. Onopgemerkte HIF-I a vlakke dui daarop dat hipoksie moontlik nie in hierdie konteks betrokke is nie. Mitokondriale respiratoriese data dui aan dat TB-infeksie of medikasie veroorsaak dat PBMC's suurstofverbruik van ATP-produksie na protonlek erskuif. Die lae kompleks-4 gekoppelde respirasie dui daarop dat mitokondriale inhoud en biogenese verminder is. Laastens die verminderde oorblywende suurstofverbruik dui aan dat die gestresde PBMC's, as gevolg van die ernstige TB of medikasie, vergoed deur die gebruik van suurstof op nie-mitokondriale paaie te verminder. Masters 2023-02-28T20:58:39Z 2023-08-30T13:10:50Z 2023 2023-02-28T20:58:39Z 2023-08-31T09:18:50Z 2023-02-28T20:58:39Z 2023-08-31T09:18:50Z 2023-03 Thesis https://scholar.sun.ac.za/handle/10019.1/128481 en_ZA Stellenbosch University application/pdf 192 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Pulmonary hypertension Tuberculosis -- Complications Mitochondrial pathology UCTD Payne, Carmen-Marie The involvement of disrupted mitochondrial pathways in pulmonary arterial hypertension as a tuberculosis sequela in a South African cohort. |
| title | The involvement of disrupted mitochondrial pathways in pulmonary arterial hypertension as a tuberculosis sequela in a South African cohort. |
| title_full | The involvement of disrupted mitochondrial pathways in pulmonary arterial hypertension as a tuberculosis sequela in a South African cohort. |
| title_fullStr | The involvement of disrupted mitochondrial pathways in pulmonary arterial hypertension as a tuberculosis sequela in a South African cohort. |
| title_full_unstemmed | The involvement of disrupted mitochondrial pathways in pulmonary arterial hypertension as a tuberculosis sequela in a South African cohort. |
| title_short | The involvement of disrupted mitochondrial pathways in pulmonary arterial hypertension as a tuberculosis sequela in a South African cohort. |
| title_sort | involvement of disrupted mitochondrial pathways in pulmonary arterial hypertension as a tuberculosis sequela in a south african cohort |
| topic | Pulmonary hypertension Tuberculosis -- Complications Mitochondrial pathology UCTD |
| url | https://scholar.sun.ac.za/handle/10019.1/128481 |
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