Saudi Cultural Missions Theses & Dissertations
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Item Restricted Investigating Pathological Remodelling in Metabolic Stress-Induced Heart Failure(Saudi Digital Library, 2025-06-17) Samman, Sultan; Wang, Xin; Zi, MinBackground Metabolic syndrome, comprising obesity, type 2 diabetes mellitus, and hypertension, is strongly associated with mitochondrial dysfunction, a major pathogenic mechanism in the progression of heart failure (HF). Emerging evidence suggests that elevated accumulation of trimethylamine N-oxide (TMAO) contributes to mitochondrial dysfunction, thereby exacerbating HF development. However, the underlying mechanisms by which TMAO promotes mitochondrial dysfunction and HF remain unclear. Aims: 1. Establish and optimise mouse models of HF that replicate the characteristic features of human heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF) induced by metabolic stress. 2. Investigate the role of TMAO-induced mitochondrial dysfunction in HF progression. 3. Examine the combined effects of palmitic acid (PA) and TMAO in cardiomyocytes. 4. Test the therapeutic potential of ZLN005 in restoring mitochondrial function under metabolic stress. 5. Assess the effect of TMAO on intracellular calcium (Ca²⁺) handling in cardiomyocytes. Methods: Wild-type mice were divided into three experimental groups: (1) a control group fed a standard chow diet (CHOW group); (2) a group fed a high-fat diet (HFD) combined with nitric oxide synthase (NOS) inhibition using N^ω-nitro-L-arginine methyl ester hydrochloride (commonly known as L-NAME), administered via drinking water, to induce hypertension (HFD+L-NAME group); and (3) a group fed a modified Western diet (MWD), consisting of a standard Western diet (WD) supplemented with TMAO, in combination with L-NAME (MWD+L-NAME group). Cardiac structural and functional changes were evaluated at weeks 5 and 25, alongside histopathological and mitochondrial assessments. In vitro, the effects of combined TMAO and PA exposure on reactive oxygen species production, fatty acid (FA) metabolism, and mitochondrial function were assessed in H9C2 cardiomyocytes. In addition, the impact of TMAO on intracellular Ca²⁺ handling was investigated. Results The HFD+L-NAME group exhibited features consistent with human HFpEF, including left ventricular (LV) hypertrophy, fibrosis, diastolic dysfunction, and moderate mitochondrial abnormalities. In contrast, the MWD+L-NAME group displayed more pronounced LV hypertrophy, fibrosis, and systolic dysfunction. This group also showed decreased ATP production and severe mitochondrial dysfunction, characterised by morphological alterations, reduced fatty acid oxidation capacity, and downregulation of mitochondrial regulatory genes, closely mirroring human HFrEF. In H9C2 cells, co-exposure to TMAO and PA induced oxidative stress, disrupted FA metabolism, promoted lipid accumulation, and impaired mitochondrial function, while ZLN005 mitigated these effects. Furthermore, TMAO dysregulated intracellular Ca²⁺ handling. Conclusions: TMAO exacerbates mitochondrial dysfunction and contributes to HF progression. The MWD+L-NAME model may serve as a valuable preclinical tool for studying HFrEF and its underlying mechanisms. Moreover, targeting mitochondrial dysfunction with ZLN005 shows promise as a therapeutic strategy to improve HF outcomes.25 0