Summary of Laboratory Research
The principal aim of Professor Mason’s scientific research is to establish a more detailed understanding of the mechanisms regulating vascular cytoprotection, in order to facilitate the rational design of novel therapies by which vascular endothelium can be conditioned to minimise vascular injury, EC dysfunction and subsequent atherogenesis in patients with systemic inflammatory disease. The group currently employs in vitro and in vivo cellular and molecular biology techniques, making use of a variety of human and murine primary large and small vessel endothelial cells. An important component of this work is to determine how drugs including statins, rapamycin, cyclosporine, PPAR agonists and cyclo-oxygenase antagonists affect cytoprotective signalling pathways in vascular endothelial cells.
In recent years Professor Mason’s group has delineated signalling pathways regulating the expression of decay-accelerating factor and CD59, identifying them as inducible regulators of complement activation on the endothelial cell surface, which act to enhance cytoprotection against complement-mediated injury. This led to work identifying VEGF-R2, PKCα, PKCε and p38 MAPK as key components of the VEGF-induced signalling pathway for DAF regulation, and the demonstration that the immunosuppressive drugs cyclosporin A and rapamycin have differential effects on this pathway. Subsequent studies have demonstrated that PKCε acts downstream of PI-3K and forms a signalling complex with Akt, acting co-dependently to protect primary human vascular EC against apoptosis, through induction of the anti-apoptotic protein Bcl-2.
The development of a model in the laboratory through which endothelial cells can be exposed to prolonged laminar or oscillatory shear stress has allowed a more physiologically relevant in vitro model to be developed. Using this approach we have demonstrated that expression of the complement regulatory protein CD59 is differentially regulated by laminar or oscillatory shear, via an ERK5 and KLF2-dependent pathway, and have confirmed these findings in vivo. This observation suggests that CD59 expression may be a contributory factor in the protection afforded by laminar shear against atherogenesis.
News article on our research
Heme oxygenase-1 is an important area of on-going study for the group. Catabolism of free heme by HO-1 generates CO, biliverdin and free iron, and these end-products are responsible for much of the biologic activity of HO-1, including anti-inflammatory, anti-apoptotic, and anti-oxidant effects. We have recently reported that induction of HO-1 by statins is differentially regulated in vascular endothelium exposed to laminar and oscillatory shear stress, proving the principle that biomechanical signalling influences endothelial responsiveness to pharmacological agents. We have also established a link between HO-1 activity and resistance to complement-mediated injury. In this collaborative study with Miguel Soares (Gulbenkian Institute, Portugal), analysis of cardiac EC isolated from Hmox1-/- mice revealed a 60% reduction in DAF expression as compared to Hmox1+/+ EC, and Hmox1-/- cells showed enhanced sensitivity to complement. This led us to propose that modulation of complement activity through induction of DAF expression is an important component of the cytoprotective effects of HO-1 and its products.
