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    Investigating the molecular mechanism of endothelial erosion of atherosclerotic plaques

    Satta, Sandro (2019) Investigating the molecular mechanism of endothelial erosion of atherosclerotic plaques. Doctoral thesis (PhD), Manchester Metropolitan University.


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    Nearly a third of heart attacks are caused by endothelial erosion, where the endothelial layer overlying atherosclerotic plaques detaches, initiating blood clot formation. Understanding the processes involved that mediate plaque erosion is the central aim of this research, in particular, the signalling pathways involved in endothelial cell (EC) dysfunction. Endothelial dysfunction caused by the combined action of inflammatory mediators and oxidants derived from cigarette smoke are known to promote coronary atherosclerosis and increase the likelihood of myocardial infarctions and strokes. Endothelial dysfunction is modified by the hemodynamic environment that the endothelial cell is exposed to, with disturbed flow found at bifurcations and curved sections of artery amplifying the effects. This plays a major role in the initiation and progression of atherosclerosis, with disease developing and progressing most rapidly in regions of oscillatory, low and disturbed wall shear stress. This reduces the bioavailability of nitric oxide as well as increasing oxidant stress, the magnitude of response to inflammatory cytokines, rates of apoptosis and permeability. On the contrary, normal physiological shear stress (12–16 dynes/cm2 in the coronary circulation) induces an athero-protective phenotype in endothelial cells predominantly mediated by activation of transcription factors KLF2, KLF4 and NRF2, all of which combine to activate a program of gene expression and epigenetic changes that reduces endothelial dysfunction. Endothelial erosion tends to occur overlying stenotic atherosclerotic plaques, exposed to very elevated levels of shear stress. Overexpression of NRF2 and NRF2 regulated genes OSGIN 1 and 2 promote EC detachment. In addition, expression of OSGIN1 and OSGIN2 increased under these conditions and also in the aortas of mice exposed to cigarette smoke. Sustained high level expression of OSGIN1+2 resulted in cell cycle arrest, induction of senescence, loss of focal adhesions and actin stress fibres, and dysregulation of autophagy. Furthermore, EC detachment observed by overexpression of either NRF2 or OSGIN1+2 did not depend on apoptosis and could be partially rescued by inhibition of HSP70 using Ver155008, or AMP kinase activation using metformin. These findings demonstrate that under elevated flow, smoking-induced hyperactivation of NRF2 can trigger endothelial cell detachment, highlighting a novel mechanism that could contribute to ACS involving endothelial erosion overlying stenotic plaques.

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