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Molecular and cellular mechanisms implicated in the regulation of cellular PMCA expression during pulmonary arterial hypertension
Ihugba, Jude C
Ihugba, Jude C
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2022
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Pulmonary arterial hypertension (PAH) is a rare, life-threatening disorder typified by elevated pulmonary vascular resistance, right ventricular hypertrophy, right heart failure and ultimately death. This disease has no current cure and available therapies alleviate vasoconstriction but do not address the disorder associated vascular remodelling. Amplified activity of pro-inflammatory cytokines has been linked to PAH development and progression. The aberrant re-modelling of the vasculature is in part dependent on the altered immune response driven by elevated synthesis of cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and interleukin (IL)-6 which are known inducers of PAH. Furthermore, the apoptotic pathway driven by TNF-α has been shown to be calcium dependent, and several studies have confirmed the increased concentration of cytosolic calcium as a key molecular influence in cell mediated vasoconstriction and proliferation. This necessitates the need for determination of the activity of calcium ion regulators. The Plasma Membrane Calcium ATPase (PMCA) proteins are high affinity pumps which extrude calcium ions extracellularly. Four PMCA Genes have been characterized (PMCA 1, 2, 3 and 4). PMCA 1 and 4 are highly expressed in the vasculature particularly, in endothelial and smooth muscle cells. In this study, the contributory role of the PMCA genes to the development of PAH was determined. The results show that pro-inflammatory inducers of PAH elicited a significant time and dose dependent reduction (~ 40-50% reduction) of PMCA4 in human pulmonary artery endothelial cells at the mRNA and protein level. Further data obtained equally show that the silencing of PMCA4 in pulmonary artery endothelial cells (PAEC) sensitized PAEC to TNF-α induced apoptosis; approximately 30% more apoptotic cells were noted in PMCA4 silenced PAEC in the presence of TNF-α. This suggests that PMCA4 shields PAEC to apoptosis in the vasculature. The results obtained demonstrate that PMCA4 contributes to initial apoptosis driven loss of endothelial cells which is regarded as an important feature in the development of PAH through yet to be elucidated mechanisms.
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Ihugba, J.C. (2022) Molecular and cellular mechanisms implicated in the regulation of cellular PMCA expression during pulmonary arterial hypertension. University of Wolverhampton. http://hdl.handle.net/2436/624966
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Thesis or dissertation
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en
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A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy.
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Attribution-NonCommercial-NoDerivatives 4.0 International