Proliferative disorders, inflammation and cardioprotection in the cardiovascular system

My research centres on the study of vascular pathologies and therapy aimed at improving the outcome of interventional procedures such as vein grafting, balloon angioplasty and stent implantation. With the high prevalence of diseases such as atherosclerosis and peripheral vascular disease in the developed world, as well as the rise in diabetes which predisposes individuals to cardiovascular disease, this area of research is highly topical and likely to remain so for the foreseeable future

Inflammation and vascular disease

We are investigating the effect of modified lipids and their involvement in neointima formation in the mouse. These lipids are formed by the action of myeloperoxidase in inflamed vessel walls and may contribute to changes in smooth muscle cell proliferation and migration. We are using a mouse wire injury model to assess effects on smooth muscle proliferation and migration and vessel histology. In collaboration with Dr Corinne Spickett and Dr Andy Pitt (Aston University) we can analyse the chlorination of lipids and synthesise lipids required for the project.
Another area of interest is in vein grafting and we have refined a model to study this. We have studied the time course of neointimal hyperplasia and the role of iNOS in driving this response and are currently investigating the role of mast cells in neointimal hyperplasia. For this we have been using a mast-cell deficient mouse and developed a double knockout on the ApoE atherosclerotic background. In collaboration with Professor Andrew Baker we are also using this model to investigate the role of microRNAs (MiRs) in vein grafting.

Stent based drug delivery

The vast majority of angioplasty procedures now involve implantation of a stent. Local delivery of drugs coated onto the stent is an attractive strategy to limit in-stent regrowth and re-narrowing of the vessel. In addition to an in vitro model of stenting which we have used to measure electrical impedance using the stent itself, we have a rabbit and a pig model of in vivo stenting which are both currently in use. In collaboration with Professor Andy Baker (Glasgow University), we are working to load stent with adenovirus which will then be used to carry therapeutic agents into the vessel wall. We have also tested a number of therapeutic interventions given orally (Figure 1- effect of oral MCP-1 inhibitor Bindarit on neointima area (right) compared to animals given no treatment) or via local, stent-based delivery. We are also interested in what causes late-stent thrombosis (see figure2: A –pig heart, B&C- stent showing thrombus in lumen) and whether we can develop compounds which encourage endothelial regrowth following stent implantation. In collaboration with biologists and mathematicians at Strathclyde University, we have a £500K grant from the EPSRC to develop and test a mathematical model which will be used to predict drug release from stents.

Endocannabinoids and cardioprotection

In collaboration with Professors Nigel and Susan Pyne (University of Strathclyde) we have been investigating the link between cannabinoids and sphingosine derivatives in the rat coronary artery. A successive PhD studentship and 2year project grant have yielded a huge body of data in this area which we published recently (Mair et al 2010). Endocannabinoids have a cardioprotective function but the mechanism of action is not fully understood. We reviewed the evidence for S1P mediating the cardioprotective effects of cannabinoids recently (Kennedy et al 2009) and we hope to advance this work using mouse knockouts to establish if the endocannabinoid/S1P mechanism can mediate cardioprotective effects in ex vivo hearts.

AMPK and vascular pathology

In collaboration with Dr Ian Salt (Glasgow University) and Dr Marie-Ann Ewart, we are investigating AMPK expression and function in atherosclerosis, with plans to extend this to diabetic and in-stent restenotic tissue. We are interested in how AMPK expression and function changes as atherosclerosis develops and how it may be involved in calcium regulation within the vascular smooth muscle cells. We also intend to study the changes in the biochemical pathways in response to AMPK activation as atherosclerosis develops in the mouse and also to use cultured vascular cells from normal and diabetic patients to assess if AMPK could link diabetes and the higher incidence of atherosclerosis in these patients.

PEA-15 and smooth muscle proliferation

In collaboration with Professor Graeme Nixon at Aberdeen University, we have obtained a grant from the MRC to investigate the function of a cytoplasmic anchoring protein known as PEA-15. We have PEA-15 knockout mice and we intend to investigate the how PEA-15 regulates MAPK activity and how this translates to smooth muscle proliferative activity in a mouse model of vascular injury

 Publications

1. Kennedy S, Preston AA, McPhaden AR, Miller AM,  Wainwright CL, Wadsworth RM. Correlation of changes in nitric oxide synthase, superoxide dimutase and nitrotyrosine with endothelial regeneration and neointimal hyperplasia in the balloon-injured rabbit subclavian artery.  Coron Artery Dis 2004;15:337-346.
2. Kennedy S, Wadsworth RM, Wainwright CL. Locally administered anti-proliferative drugs inhibit hypercontractility to serotonin in balloon-injured pig coronary artery. Vascul Pharmacol 2006;44:363-371.
3. Lim SY, Tennant GM, Kennedy S, Wainwright CL, Kane KA. Activation of mouse protease-activated receptor-2 induces lymphocyte adhesion and reactive oxygen species generation. Br J Pharmacol 2006;149:591-599.
4. Dever G, Wainwright CL, Kennedy S, Spickett CM. Fatty acid and phospholipid chlorohydrins cause cell stress and endothelial adhesion.  Acta Biochim Pol 2006;53:761-768.
5. Dever G, Tennant GM, Rush C, Kennedy S, Spickett CM, Wainwright CL. The NO-donating pravastatin derivative (NCX 6550) reduces lymphocyte adhesion and ROS generation in normal and atherosclerotic mice.  J Pharmacol Exp Ther 2007;320:419-426.
6. Maffia P, Zinselmeyer BH, Ialenti A, Kennedy S, Baker AH, McInnes IB, Brewer JM, Garside P. Images in cardiovascular medicine. Multiphoton microscopy for 3-dimensional imaging of lymphocyte recruitment into apolipoprotein-E-deficient mouse carotid artery.  Circulation 2007;115:e326-e328.
7. Kennedy S, Burke SG, Preston AA, McPhaden AR. Nitric oxide generation by NO donors is enhanced following balloon injury in the porcine coronary artery. Endothelium 2007;14:105-113.
8. McCormick C, Wadsworth RM, Jones RL, Kennedy S. Prostacyclin analogues: the next drug-eluting stent? Biochem Soc Trans 2007;35:910-911.
9. Watt J, Wadsworth RM, Kennedy S, Oldroyd KG. Pro-healing drug-eluting stents: a role for antioxidants? Clin Sci (Lond.) 2008;114:265-273.
10. Coats P, Kennedy S, Pyne S, Wainwright CL, Wadsworth RM. Inhibition of non-Ras protein farnesylation reduces in-stent restenosis. Atherosclerosis 2008;197:515-523.
11. Tennant G, Wadsworth RM, Kennedy S. PAR-2 mediates increased inflammatory cell adhesion and neointima formation following vascular injury in the mouse. Atherosclerosis 2008;198:57-64.
12. Dever GJ, Wainwright CL, Kennedy S, Spickett CM. Phospholipid chlorohydrin induces leukocyte adhesion to ApoE -/- mouse arteries via upregulation of P-Selectin. Free Radic Biol Med 2008;44:452-463.
13. Erridge C, Kennedy S, Spickett CM, Webb DJ. Oxidised phospholipid inhibition of toll like receptor (TLR) signalling is restricted to TLR2 and TLR4 – Roles for CD14, LPS-binding protein and MD2 as targets for specificity of inhibition. J Biol Chem 2008;283:24748-24759.
14. Farmer DGS, Kennedy S. RAGE, vascular tone and vascular disease. Pharmacol Ther 2009;124:185-194.
15. Lim SY, Wainwright CL, Kennedy S, Kane KA. Activation of protease activated receptor-2 induces delayed cardioprotection in anesthetized mice. Cardiovasc Drugs Ther 2009;23:519-520.
16. Kennedy S, Kane KA, Pyne NJ, Pyne S. Targeting sphingosine-1-phosphate for cardioprotection. Curr Opinion Pharmacol 2009;9:194-201.
17. McCormick CM, Jones RL, Kennedy S, Wadsworth RM. Activation of prostanoid EP receptors by prostacyclin analogues in rabbit iliac artery: implications for anti-restenotic potential.  Eur J Pharmacol 2010;641:160-167.
18. Mair KM, Robinson E, Kane KA, Pyne S, Pyne NJ, Kennedy S. Interaction between anandamide and sphingosine-1-phosphate in mediating vasorelaxation in rat coronary artery. Br J Pharmacol 2010;161:176-192.
19. Wu J, Wadsworth RM, Kennedy S. Inhibition of iNOS promotes vein graft neoadventitial inflammation and remodelling.  J Vasc Res 2011;48:141-149.
20. Shedden L, Kennedy S, Wadsworth RM, Connolly P.  Towards a self-reporting coronary artery stent – Measuring neointimal growth associated with in-stent restenosis using electrical impedance techniques. Biosensors & Bioelectronics 2010;26:661-666.
21. Grassia G, Maddaluno M, Musilli C, De Stefano D, Carnuccio R, Di Lauro MV, Parratt CA, Kennedy S, Di Meglio P, Ianaro A, Maffia P, Parenti A, Ialenti A.  The IκB kinase inhibitor nuclear factor-κB essential modulator-binding domain peptide for inhibition of balloon injury-induced neointimal formation. Arterioscler Thromb Vasc Biol 2010;30:2458-2466.
22. Ialenti A, Grassia G, Gordon P, Maddaluno M, Di Lauro MV, Baker AH, Guglielmotti A, Colombo A, Biondi G, Kennedy S, Maffia P. Inhibition of in-stent stenosis by oral administration of bindarit in porcine coronary arteries. Arterioscler Thromb Vasc Biol 2011;31:2448-2454.
23. Ewart AM, Kennedy S. AMPK and vasculoprotection. Pharmacol Ther 2011;131:242-253.
24. Watt J, Greig F, Ewart MA, Wadsworth RM, Oldroyd KG, Kennedy S. The effect of reactive oxygen species on whole blood aggregation and the endothelial cell-platelet interaction in patients with coronary heart disease. Thromb Res 2012;130:210-215.
25. Watt J, Kennedy S, McCormick CM, Agbani EO, Mullen A, Czudaj P, Behnisch B, Wadsworth RM, Oldroyd KG, 2012 Stent-based delivery of succinobucol in a porcine coronary model. Catheter Cardiovasc. Interv. 2012 May 14 (EPub ahead of print)
26. Greig FH, Kennedy S, Spickett CM. Physiological effects of oxidized phospholipids and their cellular signalling mechanisms in inflammation. Free Radic Biol Med 2012;52:266-280.
27. Ewart AM, Kennedy S. Diabetic cardiovascular disease – AMP-activated protein kinase (AMPK) as a therapeutic target. Cardiovasc Hematol Agents in Med Chem 2012;10:190-211.
28. Kennedy S, Wu J, Wadsworth RM, Lawrence CE, Maffia P. Mast cells and vascular diseases. Pharmacol Ther. 2013; 138:53-65.