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Title: The regulation of angiotensin-converting enzyme 2 (ACE2)
Author: Clarke, Nicola Elizabeth
ISNI:       0000 0004 2747 7589
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2012
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The levels of ACE2 at the cell surface are regulated by cleavage at the plasma membrane Angiotensin-converting-enzyme-2 (ACE2) acts as the protective arm of the renin-angiotensin system (RAS). ACE2 counterbalances the actions of ACE by metabolising the catalytic product of ACE, angiotensin 11 (Ang 11), a vasoconstrictor into Ang-(1-7), a vasodilatory peptide. ACE2 has been found to mediate effects, independently of Ang-(1-7), through non-catalytic actions. The aim of this study was to use cell biology to identify factors regulating ACE2 expression and investigate a potential non-catalytic interaction with integrin β1. Cells endogenously expressing ACE2, Huh7 cells, and HEK cells overexpressing ACE2 or tACE were used to probe for an interaction between the angiotensinases and integrins. Both ACE and ACE2 were found to bind integrin subunits, in an RGD-independent manner and they can act as cell-adhesion substrates. The cellular expression of ACE2 on the cell-surface was found to co-localise with integrin β1 and to enhance cell adhesion. Furthermore, treatment of cells with purified ACE2 but not Ang-(1-7), resulted in suppression of integrin signalling mediated by FAK in Huh7 cells. These results suggest that ACE2 plays a role in cell-cell interactions, possibly acting to fine-tune integrin signalling. Hence the cell surface location of ACE2 may be important for some of its protective effects. ( shedding) and levels of this shed form of ACE2 have been correlated with myocardial dysfunction. Herein it is shown that, Ang 11 acts as an endogenous stimulus of shedding by upregulating the expression of ADAM17 at the cell membrane in Huh7 cells. As such, it is possible that some of the pathological effects of Ang 11 are mediated through disruption of integrin signalling caused by a loss of ACE2 at the cell membrane. Although, understanding the control of ACE2 expression is of therapeutic relevance to diseases including cardiovascular and acute respiratory diseases, few studies have investigated the cellular regulation of ACE2. Several factors regulating ACE2 expression in Huh7 cells were identified in this thesis, including up-regulation by a proinflammatory cytokine and modulation by the action of a microRNA. Furthermore, it was found that the expression of ACE2 transcript was modified by hypoxic conditions and cell energy-stress, suggesting regulation by AMP kinase. Energy-stress-induced increases in ACE2 expression were determined to be under the control of SIRT1.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available