King's College London - Professor Jon C Kentish

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Professor Jon C Kentish

Professor of Cellular Cardiology

KentishJon140x180 Cardiovascular Division
The Rayne Institute
4th Floor, Lambeth Wing
St Thomas' Hospital
Lambeth Palace Road
London SE1 7EH
Tel: 020 7188 5611
E-mail: jon.kentish@kcl.ac.uk

Biography

Professor Jon Kentish obtained a BA (subsequently MA) in Physiological Sciences from the University of Oxford and a PhD in Physiology from the University of London, before taking up post-doctoral positions at the University of Leeds and then University College London. After being awarded a British Heart Foundation Senior Fellowship, he joined the United Medical and Dental Schools (now incorporated into King’s College London) in 1989. He was promoted to Senior Lecturer in 1993, Reader in 1997, and Professor of Cellular Cardiology in 2005. From 2001 to 2006 he was Co-ordinator of the Medical Research Council Co-operative Group on Cellular Mechanism of Myocardial Function and Dysfunction.

Professor Kentish is currently a member of the committee of the International Society for Heart Research – European Section (from 2009) and was a committee member of the British Society for Cardiovascular Research (1982 - 1985). He is also a member of the International Society for Heart Research (since 1977), Biophysical Society (1979), British Society for Cardiovascular Research (1979), The Physiological Society (1985) and the British Pharmacological Society (2000). Professor Kentish is on the editorial boards of the Journal of General Physiology (from 1989) and Frontiers in Physiology (from 2010), has served on the editorial board of Basic Research in Cardiology (1990 - 1994), and is a Critical Reviewer of Grays Anatomy. Together with Drs Chambers and Fallouh, he holds a patent for a novel cardioprotective solution for use in cardioplegia.

Professor Kentish is the organiser of the 4BBM0107 Fundamentals of Pharmacology course for Common Year One students in the School of Biomedical Sciences (420 students). He is a past recipient of the prize for the Best Preclinical Lecturer for the MBBS (medical) course.

Research interests

Jon Kentish leads the Cardiac Muscle Research Group, whose research focus is to elucidate the key molecular and cellular mechanisms by which the contractile properties of the heart muscle are controlled in the short-term by factors such as sarcomere length and hormones, and in the long-term by disease. A major theme is to measure the contractile properties of the myofibrils within “skinned” (permeabilised) cardiac muscles or single myocytes, within which the ionic environment of the myofibrils can be controlled precisely. Skinned cardiac preparations are used to measure myofibrillar properties such as: passive stiffness; Ca²⁺-activated isometric force and cycling kinetics of myosin cross-bridges; activation and relaxation kinetics (using flash photolysis of “caged” Ca²⁺compounds). Other techniques used include simultaneous measurement of contraction and intracellular pH or Ca²⁺ in intact myocytes (by fluorescence microspectrophometry), and the use of transgenic mice, recombinantly-engineered proteins, and phosphorylation site-specific antibodies to isolate specific phosphorylation pathways. The main current research projects are as follows.

1. Control of myofilament contractile performance by phosphorylation

Phosphorylation of myofibril proteins, in particular troponin-I (TnI) and myosin binding protein MyBP-C (MyBP-C), by intracellular protein kinases is a key regulatory pathway for the control of the myofibrillar Ca²⁺ sensitivity and of the rate of cycling of myosin crossbridges. In turn, these two factors determine the contractile activity of the heart and regulate the amount of blood expelled from the heart in each beat. In addition, phosphorylation of the “molecular spring” protein, titin, controls the passive stiffness of the myofibrils and so regulates compliance of the heart chambers as they fill with blood. Using skinned cardiac muscles (Figure 1), we showed recently that two novel protein kinases, PKD and RSK, phosphorylate the myofibrils at different sites on MyBP-C, yet have a similar effect to accelerate crossbridge kinetics (Bardswell et al, 2010; Cuello et al, 2010). Research is underway to determine the molecular mechanism of these changes and to find out the relevance of these effects for the function of the intact heart in health and disease.

Figure 1.
Upper panel: A skinned cardiac muscle attached to a force transducer and servomotor.
Lower panel: During activation by Ca²⁺, the skinned muscle is shortened by 20% for 40 ms, which causes detachment of myosin crossbridges from actin, so force falls to zero. The rise of force reflects the rate at which the crossbridges re-attach to actin.

2. Passive and active contractile properties of the myofibrils in human heart disease

Changes in the expression and phosphorylation of myofibrillar proteins have important functional consequences in heart disease. We are able to isolate muscles or single myocytes (e.g. Figure 2) from small biopsies taken from patients who are undergoing heart surgery. Using such preparations, we have demonstrated that the stiffening of heart muscle found in hypertrophied myocardium is the result of increases in collagen, rather than changes in the stiffness of the myocytes (Chaturvedi et al, 2010). Skinned myocytes from hypertrophied myocardium exhibit a reduced maximum force, which would tend to reduce the ejection of blood (systolic dysfunction), and a higher myofibrillar Ca²⁺ sensitivity, which would tend to cause slower muscle relaxation (diastolic dysfunction). Thus the contractile properties of the myofibrils are key contributors to the pathophysiology of heart disease (Hoskins et al, 2010).

Figure 2.
Upper panel: A human single skinned myocyte attached to a force transducer and servomotor.
Lower panel: a myocyte being stretched to test its passive stiffness.

Group members

Dr S-J Holohan
Dr S C Bardswell
Dr M Marshall (jointly with Professor Shah)

Selected recent publications

CUELLO, F., BARDSWELL, S.C., HAWORTH, R.S., EHLER, E.,SADAYAPPAN, S., KENTISH, J.C. & AVKIRAN, M. (2010). Novel role for p90 ribosomal S6 kinase in the regulation of cardiac myofilament phosphorylation. Journal of Biological Chemistry 286, 5300–5310. [Link]
HOSKINS, A.C., JACQUES, A., BARDSWELL, S.C., MCKENNA W.J, TSANG V, DOS REMEDIOS C., EHLER, E., ADAMS, K., JALILZADEH, S., AVKIRAN, M., WATKINS, H., REDWOOD C., MARSTON, S.B. & KENTISH, J.C. (2010). Normal passive viscoelasticity but abnormal myofibrillar force generation in human hypertrophic cardiomyopathy. Journal of Molecular and Cellular Cardiology. 49, 737-745. [Link]
PATRICK, S.M., HOSKINS, A.C., KENTISH, J.C., WHITE, E., SHIELS, H.A., CAZORLA, O. (2010). Enhanced length-dependent Ca2+ activation in fish cardiomyocytes permits a large operating range of sarcomere lengths. Journal of Molecular and Cellular Cardiology 48, 917-924. [Link]
CHATURVEDI, R.R., HERRON, T., SIMMONS, R., SHORE, D. KUMAR, P., SETHIA, B., CHUA, F., VASSILIADIS, E., & KENTISH, J.C. (2010). Passive stiffness of myocardium from congenital heart disease and implications for diastole. Circulation 121, 979-988. [Link]
BARDSWELL, S.C., CUELLO, F., ROWLAND, A.J., GAUTEL, M., WALKER, J.W. KENTISH, J.C., & AVKIRAN. M. (2010). Distinct sarcomeric substrates are responsible for protein kinase D-mediated regulation of cardiac myofilament Ca2+ sensitivity and crossbridge cycling.. Journal of Biological Chemistry 285, 5674–568. [Link]
MARSHALL, M., ANILKUMAR, N., LAYLAND, J., WALKER, S,J., KENTISH, J.C., SHAH, A.M. & CAVE, A.C. (2009). Protein phosphatase 2A contributes to the cardiac dysfunction induced by endotoxaemia. Cardiovascular Research 82, 67-76. [Link]
DYER, E., JACQUES, A., HOSKINS, A.C., WARD, D.G., GALLON, C.E., MESSER, A.F., KASKI, J.P., BURCH, M., KENTISH, J.C., MARSTON, S.B. (2009). Functional analysis of a unique troponin C mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle. Circulation: Heart Failure 2, 456-464. [Link]
FALLOUH, H., KENTISH, J.C. & CHAMBERS, D.C. (2009). Targeting for cardioplegia: arresting agents and their safety. Current Opinion in Pharmacology 9, 220-226. [Link]
JACQUES, A., HOSKINS, A.C., KENTISH, J.C. & MARSTON, S.B. (2008). From genotype to phenotype: a longitudinal study of a patient with hypertrophic cardiomyopathy due to a mutation in the MYBPC3 gene. Journal of Muscle Research & Cell Motility 29, 239-246. [Link]
CUELLO, F., BARDSWELL, S.C., HAWORTH, R.S., YIN, X., LUTZ, S., WIELAND. T., MAYR, M., KENTISH, J.C., AVKIRAN, M. (2007). Protein kinase D selectively targets cardiac troponin I and regulates myofilament Ca2+ sensitivity in ventricular myocytes. Circulation Research 100, 864-873. [Link]
BRENNAN, J.P., BARDSWELL, S.C., BURGOYNE, J.R., FULLER, W., SCHRÖDER, E., WAIT, R., BEGUM, S., KENTISH, J.C. & EATON, P. (2006) Oxidant-induced activation of type I PKA is mediated by RI subunit interprotein disulphide bond formation. J. Biological Chemistry 281, 21827-21836. [Link]
HERRON, T.J., KUNST, G., ROSTKOVA, E., GAUTEL, M., CHATURVEDI, R., KENTISH, J.C. (2006). Sarcomere length - dependent regulation of cardiac contraction by myosin binding protein-C. Circulation Research 98, 1290-1298. [Link]
LAYLAND, J., CAVE, A.C., GRIEVE, D.J., SPARKS, E., KENTISH, J.C., SOLARO, R.J. & SHAH, A.M. (2005). Protection against endotoxaemia-induced contractile dysfunction in mice with cardiac-specific expression of slow skeletal troponin I. FASEB J. 19, 1137–1139. [Link]
HAWORTH, R.S., HERRON, T.J., CUELLO, F., GAUTEL, M., KENTISH, J.C. & AVKIRAN, M. (2004). Protein kinase D is a novel mediator of cardiac troponin I phosphorylation and regulates myofilament function. Circulation Research 95, 1091-1099. [Link]

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