Saudi Cultural Missions Theses & Dissertations
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Item Embargo Investigating the ability of statin-mediated ERK5 activation to protect cardiac microvascular endothelial cells and cardiomyocytes against the adverse effects of doxorubicin.(Saudi Digital Library, 0025-04-10) Almaghrabi, Shrouq; Cross, MichaelDoxorubicin is a widely used chemotherapeutic agent known for its efficacy against various cancers; however, its clinical utility is limited by cardiotoxic side effects that involve both endothelial dysfunction and direct cardiomyocyte damage. This doctoral research investigates the protective role of statins—specifically simvastatin and atorvastatin—in mitigating doxorubicin-induced toxicity through activation of the ERK5 signaling pathway. Using human and mouse cardiac microvascular endothelial cells (HCMECs and MCMECs), as well as human cardiomyocyte-like AC16 cells, the study demonstrates that statins restore ERK5 phosphorylation and upregulate vasoprotective transcription factors KLF2 and KLF4. These molecular changes were associated with decreased inflammatory marker expression, preserved tight junction integrity, and improved cellular viability. The findings highlight a novel therapeutic potential for statins in preserving cardiovascular health during chemotherapy and underscore the significance of ERK5 as a molecular target for cardioprotection.29 0Item Restricted Electrophysiological and cellular analysis of filamin-C mutations causing cardiomyopathy using human iPSC-derived cardiomyocytes(Saudi Digital Library, 2023) Taleb, Yaqob Samir A; Lambiase, PierArrhythmogenic Cardiomyopathy (AC) is a genetic cardiac disease resulting from different mutations within proteins constituting the intercalated disc, including desmosomal and non-desmosomal proteins. Recent studies have revealed that mutations in filamin-C (FLNC) may lead to AC. The arrhythmogenesis and electrophysiological effects of FLNC-related AC are incompletely understood. Therefore, the aim of this study is to assess the potential electrophysiological consequences of FLNC loss as occurs in AC in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Specifically, I aimed to characterise abnormal electrical activity and the expression and function of key proteins in cardiac electrical activity such as gap junction protein connexin 43 (Cx43). hiPSC-CMs were differentiated and observed by immunofluorescence microscopy. Small interfering RNA (siRNA) transfection was utilised to knockdown the expression of FLNC in hiPSC-CMs. Protein analysis was performed using western blotting to confirm the knockdown efficiency. Electrophysiological properties were recorded using a multielectrode array and manual patch clamping. Optical recording of membrane potential and calcium activity from hiPSC-CMs were also carried out using parameter sensitive dyes. Silencing of FLNC led to markedly decreased immunofluorescence signals of FLNC, Cx43, desmoplakin, and junctional plakoglobin. No significant reductions were noted in the immunofluorescence signals of voltage-gated sodium channel (Nav1.5) and plakophilin-2 compared with control hiPSC-CMs. Western blotting showed the reduction of FLNC and Cx43 expression following silencing of FLNC. Knockdown of FLNC resulted in disturbances to the recorded action and field potential signals of hiPSC-CMs and arrhythmic like-events. Transfected hiPSC-CMs with siRNA-FLNC were associated with prolongation of calcium transient durations, optical action potential duration, and action potentials measured with patch clamping. The current findings indicated that loss of FLNC resulted in a complex arrhythmogenic phenotype in hiPSC-CMs.39 0