The cellular basis of age-related heart dysfunction; does oxidative stress play a role?

Improvements in diet and lifestyle have reduced the rate of premature death from lifestyle-related cardiovascular disease. However, as the average age of our population increases, so does the incidence of age-related cardiovascular dysfunction. In other words, people are now living to an age which permits the onset of age-related cardiovascular disease [1]. As the emergence of this particular pathology is relatively recent, the precise nature and underlying mechanisms are poorly understood.

The heart beats because the billions of heart cells which form heart muscle contract then relax in unison. Cell contraction is dependent on a complex sequence of events collectively known as excitation-contraction coupling (ECC). Any unwanted alterations to ECC and so cell contraction have profound consequences for whole-heart function.

We now know that alterations to ECC occur in ageing and these changes can account for many aspects of the clinical phenotypes [2-4]. However, we do not understand what mediators are responsible for these changes to cell function. A likely candidate is oxidative stress given that oxidative stress is increased in ageing [5] and is known to play a major role in the regulation and dysregulation of heart cell function including ECC [6, 7]. As such your project will investigate the role of oxidative stress in age-related alterations to heart cell function.

Through our collaboration with the University of Manchester you will have access to one of the world’s only large mammal models of ageing providing a clinically relevant, unique and valuable opportunity to elucidate the mechanisms underlying age-related cardiac dysfunction. You will isolate heart cells from this model then use conventional and confocal microscopic photometry (the use of fluorescent probes to measure the intracellular environment) to quantify levels of heart cell oxidative stress. You will use the same methods to quantify heart cell function - namely intracellular calcium handling and mechanical contractility; key components of ECC. In doing so you will address the following questions:

• To what extent is cardiac cellular oxidative stress elevated in ageing?
• What are the sources of age-related oxidative stress (mitochondrial, enzymatic or other)?
• Do levels of oxidative stress correlate with severity of change to cell function?
• Can therapeutic intervention reduce oxidative stress and restore cell function to levels comparable to youth?

You will carry out most experiments in our lab at The University of Salford becoming proficient in the use of a wide range of state-of-the-art equipment and techniques. However, you will also have opportunities to undertake additional experiments in our collaborator’s lab at the University of Manchester further expanding your skill-set, experience and contacts. You will be encouraged to present your findings at leading national and international scientific meetings and co-publish in high impact scientific journals.

This studentship is fully funded under the University of Salford Doctoral Training Alliance, applications can be made online through the website at http://www.salford.ac.uk/study/postgraduate/applying/applying-for-research

For further information on the Alliance, please visit the DTA website at www.unialliance.ac.uk/DTA
For further information on the project please contact Dr David Greensmith – [Email Address Removed]; Phone :0161 295 2170

References:
[1] A. Peeters, A.A. Mamun, F. Willekens, L. Bonneux, A cardiovascular life history, European Heart Journal, 23 (2002) 458-466.

[2] H.A. Feridooni, K.M. Dibb, S.E. Howlett, How cardiomyocyte excitation, calcium release and contraction become altered with age, Journal of molecular and cellular cardiology, 83 (2015) 62-72.

[3] J.D. Clarke, J.L. Caldwell, C.M. Pearman, D.A. Eisner, A.W. Trafford, K.M. Dibb, Increased Ca buffering underpins remodelling of Ca2+ handling in old sheep atrial myocytes, The Journal of physiology, 595 (2017) 6263-6279.

[4] K.M. Dibb, U. Rueckschloss, D.A. Eisner, G. Isenberg, A.W. Trafford, Mechanisms underlying enhanced cardiac excitation contraction coupling observed in the senescent sheep myocardium, Journal of molecular and cellular cardiology, 37 (2004) 1171-1181.

[5] T. Finkel, N.J. Holbrook, Oxidants, oxidative stress and the biology of ageing, Nature, 408 (2000) 239.

[6] D.J. Greensmith, D.A. Eisner, M. Nirmalan, The effects of hydrogen peroxide on intracellular calcium handling and contractility in the rat ventricular myocyte, Cell calcium, 48 (2010) 341-351.

[7] J. Scotcher, O. Prysyazhna, A. Boguslavskyi, K. Kistamas, N. Hadgraft, E.D. Martin, J. Worthington, O. Rudyk, P. Rodriguez Cutillas, F. Cuello, M.J. Shattock, M.S. Marber, M.R. Conte, A. Greenstein, D.J. Greensmith, L. Venetucci, J.F. Timms, P. Eaton, Disulfide-activated protein kinase G Iα regulates cardiac diastolic relaxation and fine-tunes the Frank–Starling response, Nature Communications, 7 (2016) 13187.