Thesis
Investigating the inflammatory pathways and proteomic networks in a rodent model of hypertension: exploring HMGB1 expression in the cardiac niche
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2025
- Thesis identifier
- T17525
- Person Identifier (Local)
- 202055069
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Background: Hypertension is a key risk factor for cardiac remodelling and cardiovascular disease (CVD). Remodelling involves cardiomyocytes, endothelium, vascular smooth muscle, interstitial cells, and the extracellular matrix (ECM), primarily composed of fibrillar collagen. A hallmark of myocardial remodelling is altered collagen turnover, leading to fibrosis. Excess ECM deposition can be triggered by chronic inflammation and damage-associated molecular patterns (DAMPs). High Mobility Group Box 1 (HMGB1), a DAMP elevated in cardiovascular patients, has been linked to inflammatory heart conditions and cardiac hypertrophy, but its role in hypertension and end-organ damage remains unclear. Project Aim: To assess the contribution of HMGB1 to cardiac/vascular inflammation and remodelling in an in vivo male adult rat model of chronic hypertension. Hypothesis: We hypothesised that HMGB1, particularly its high-molecular-weight isoform (HMW-HMGB1), contributes to inflammation and fibrosis during angiotensin II-induced hypertension, thereby driving cardiac remodelling. Method: To study HMGB1 contribution in vascular dysfunction, a chronic hypertension model was used. Male Sprague-Dawley rats underwent osmotic mini-pump implantation surgery, ensuring continuous infusion of Ang II for 28 days. Heart tissues were harvested to examine HMGB1 expression for inflammatory pathways. In addition to heart cross-section staining for HMGB1 localisation and collagen distribution, extracellular vesicles (EVs) were examined to explore potential HMGB1 release mechanisms. Due to low serum EV yield from Ang II rats, the human megakaryoblastic cell line (MEG-01) was employed as an in vitro surrogate model for platelet-like particle formation. Dynamic Light Scattering confirmed EV size within the expected exosomal range, and Western blotting detected HMGB1 within MEG-01 EV cargo, supporting a non-classical vesicular secretion pathway. Furthermore, shotgun liquid chromatography–mass spectrometry (LC-MS)-based proteomic profiling was performed to identify differentially expressed proteins in left ventricular tissue across Ang II, saline, and control groups, providing complementary molecular insights into cardiac remodelling. Key findings: Chronic hypertension was confirmed with increased cardiac function and changes in echocardiography measurements. Cardiac fibrosis was evident in the Ang II groups, with significant collagen fibre deposition observed using Masson’s Trichrome staining. Immunofluorescence analysis revealed enhanced HMGB1 expression and cytoplasmic re-localisation, particularly in perivascular fibrotic regions, supporting its role in inflammatory signalling. Proteomic analysis identified key molecular players, including Acta1, Cfl1, Tubb2a, Itga7, and HMGB1, that may drive cytoskeletal reorganisation and inflammatory signalling in hypertensive cardiac remodelling. These findings provide novel insights into the proteomic landscape of early-stage heart failure (pre-HF), highlighting potential molecular targets for future research and therapeutic intervention
- Advisor / supervisor
- Cunningham, Margaret
- Currie, Susan
- Resource Type
- DOI
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PDF of thesis T17525 | 2025-12-02 | Public | Télécharger |