Professor Siân Harding, Head of Group
The group is focused on the function of the failing cardiomyocyte, either in acute or chronic heart failure. Cardiomyocytes are isolated from failing human heart, usually from tissue obtained during transplant operations, or from animal models. Contraction of single cells is measured, and their response to drugs and other experimental compounds recorded. Using adenovirus to transfect the cells, we can alter levels of key signalling proteins, such as SERCA2a, phospholamban, the Na+/Ca2+-exchanger, the ß1- and ß2-adrenoceptors, G-proteins and Na+/K+-ATPase. We have been able to normalise the function of myocytes from failing human heart by these methods. One particular interest is the ß-adrenoceptor system, and the mechanism by which β-blockers improve the contraction of the failing heart. We have proposed a new mechanism where stimulus trafficking of the β2-adrenoceptor allows compounds which are normally blockers to activate a protective signalling cascade (Gong, Circulation 2002). We have also hypothesized that the protective β2AR signalling cascade is activated in Stress Cardiomyopathy, a severe but transient heart failure triggered by physical or psychological stress (Lyon, Nat. Clin. Pract. Cardiovasc. Med 2008). Mechanisms for spatial control of β1- and β2AR signalling within the cardiac myocyte are also being studied in collaboration with Dr Julia Gorelik (Science 2010). This work is linked to the Biology of the Failing Heart Theme in the BHF Centre of Research Excellence.
New therapies for the failing heart are also being explored. Genes are introduced in vivo to animal models using adenovirus or AAV and their effect on contraction of the whole heart and of individual cells determined. Our experiments are among those that have led to the identification of SERCA2a as a potential target in the failing heart (del Monte, Circulation 1999). We are leading a Gene Therapy Trial in collaboration with Harefield and Papworth Hospitals to use AAV vectors to restore SERCA2a levels in heart failure patients on ventricular assist device support.
Cell therapy for heart failure is also being explored, and we have examined the interaction between injected immature myocytes and the host myocardium as well as the limited potential of bone marrow cells to produce cardiomyocytes (Sato, Stem Cells Dev 2010). With Dr Nadire Ali we are producing robust cardiomyocyte differentiation from human embryonic stem cells and characterizing the contraction, development, growth and death of the cardiomyocytes from these and induced pluripotent stem cells (Brito-Martins, Br J Pharmacol 2008). Developing high throughput methods to explore the biology of stem cells and stem cell-derived cardiomyocytes is a collaborative venture with Prof Michael Schneider. We are also interested in the potential of these stem cell derived cardiomyocytes as a model system for cardiac disease (Abdul Kadir, J Cell Mol Med 2009) and for cardiac toxicology. We are members of the Stem Cells for Safer Medicines partnership.
Nikolaev VO, Moshkov A, Lyon AR, Miragoli M, Novak P, Paur H, Lohse MJ, Korchev YE, Harding SE, Gorelik J.Beta2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science. 2010 Mar 26;327(5973):1653-7. Epub 2010 Feb 25.
Chen QZ, Ishii H, Thouas GA, Lyon AR, Wright JS, Blaker JJ, Chrzanowski W, Boccaccini AR, Ali NN, Knowles JC, Harding SE.An elastomeric patch derived from poly(glycerol sebacate) for delivery of embryonic stem cells to the heart. Biomaterials. 2010 May;31(14):3885-93. Epub 2010 Feb 11.
Sato M, Carr CA, Stuckey DJ, Ishii H, Kanda GK, Terracciano CM, Siedlecka U, Tatton L, Watt SM, Martin-Rendon E, Clarke K, Harding SE. Functional and morphological maturation of implanted neonatal cardiomyocytes as a comparator for cell therapy. Stem Cells Dev. 2010 Jul;19(7):1025-34.
Lyon AR, MacLeod KT, Zhang Y, Garcia E, Kanda GK, Lab MJ, Korchev YE, Harding SE, Gorelik J. Loss of T-tubules and other changes to surface topography in ventricular myocytes from failing human and rat heart. Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6854-9. Epub 2009 Apr 2.
Lyon AR, Rees PS, Prasad S, Poole-Wilson PA, Harding SE. Stress (Takotsubo) cardiomyopathy--a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med. 2008 Jan;5(1):22-9. Review.