A spoonful of sugar makes the medicine go...wrong: Disruption of the intrinsic protection in the heart by hyperglycaemia

Description

Hyperglycaemia at the time a patient suffers a heart attack has been shown to cause a poorer outcome for the patient. This can be an increased infarct size, poorer long-term prognosis, increased risk of developing heart failure, but also an increased likelihood of death from the initial cardiac event.

In our laboratory, we have demonstrated that cardiac cells are more prone to arrhythmias, have reduced cell survival and reduced contractile recovery following a simulated ischaemia with elevated extracellular glucose. (Sims et al 2014, Brennan et al 2019, 2022). We have also shown that blood vessels have an increased contractile response to vasoconstrictor activity and compromised receptor desensitisation in elevated glucose concentrations (Rainbow et al 2006, Jackson et al. 2016). Together, these data suggest a mechanism by which poor outcome occurs; enhanced cardiac cell death, pro-arrhythmic settings for the cardiac cells, and increased contractile tone in the vasculature reducing coronary perfusion.

Cardioprotection is a broad term given to the ability of the myocardium to protect itself from ischaemic damage. This cardioprotection can be triggered pharmacologically with compounds such as pinacidil, adenosine and bradykinin, but can also be triggered by brief periods of ischaemia prior to a prolonged ischaemic insult, as might occur in angina prior to a heart attack. This gives the heart some protection from the ischaemic insult and manifests as a reduced infarct size, improved contractile recovery and less likelihood of developing heart failure.  However, this protection, although well established in pre-clinical animal models, fails to translate to the clinic.

Our group believes that this failure of translation of these cardioprotective interventions is due to hyperglycaemia that can occur when a patient is suffering a heart attack. The “fight-or-flight” response that occurs due to the stress will cause a significant increase in blood sugar as adrenaline will cause a release of the glycogen stores to provide energy. We have preliminary data to suggest that this glucose elevation activates cell signalling pathways that mask the cardioprotective pathways, so abolishing the protective response. This is not seen in the pre-clinical animal models as they are anesthetised and do not experience the same stress-response. Our data shows that the loss of cardioprotection in high glucose can be restored by selectively inhibiting the toxic pathways activated by high glucose (Sims et al 2014). We believe that this could be a future therapy to restore failed cardioprotective interventions that have been attenuated by the high glucose.

In this project, the student will investigate the cell signalling pathways that glucose and cardioprotection are activating. Using contractile function assays, cellular imaging, electrophysiological measurements, and whole heart Langendorff coronary ligation experiments, the student will assess the role that glucose has in masking cardioprotection. Further to this, the student will carry out analysis of the literature to determine the degree to which the glucose levels in the patients blood may have influenced outcomes in clinical trials investigating cardioprotective interventions. 

Student experience

The successful student will gain full training in a multitude of techniques, ranging from cell culture, electrophysiology measurements, NMR Metabolomics, fluorescence imaging, metabolic analysis using Seahorse analyser technology, and essential research skills including western blotting, qPCR, immunofluorescence, and ELISA.

Applicant Information

The successful applicant should have an interest in cardiovascular research and hold a minimum undergraduate qualification 2:1 or equivalent in a science or health-related subject.

All postgraduate students undertake the Post Graduate Researcher (PGR) Development Programme which aims to enhance their skills for a successful research experience and career. They are required to maintain an online record of their progress and record their personal and professional development throughout their research degree. The Liverpool Centre for Cardiovascular Science holds monthly research group meetings where students are given opportunities to present their research and meet and interact with their peers and senior researchers. Students are also encouraged to attend the seminar series to gain a breadth of knowledge from related research within the Department of Cardiovascular and Metabolic Medicine and wider research themes across our Institute.

The Institute of Life Course and Medical Science is fully committed to promoting gender equality in all activities. In recruitment we emphasize the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a silver Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives.

Research project related enquiries should be made in the first instance to Dr Richard Rainbow (richard.rainbow@liverpool.ac.uk). All general enquiries should be directed to Mrs Eleanor Toole (ilcamspgradmin@liverpool.ac.uk).

To apply please send your CV and a covering letter to Dr Richard Rainbow (richard.rainbow@liverpool.ac.uk).

Availability

Open to students worldwide

Funding information

Self-funded project

This is a self-funded PhD opportunity open to students worldwide. Candidates with scholarships awarded by external funding bodies/national governments are invited to apply. Information on research degree fees and how to fund your PhD are available on the University website at https://www.liverpool.ac.uk/study/postgraduate-research/fees-and-funding/

 

Supervisors

References

BRENNAN S, ESPOSITO S, ABDELAZIZ MIM, MARTIN CA, MAKWANA SB, SIMS MW, SQUIRE IB, SHARMA P, CHADWICK AE & RD RAINBOW, (2022) Selective PKC inhibition switches time-dependent glucose cardiotoxicity to cardioprotection. Front Cardiovasc Med (in press)

BRENNAN S, CHEN S, MAKWANA S, MARTIN CA, SIMS MW, ALONAZI ASA, WILLETS JM, SQUIRE IB & RAINBOW RD. 2019. A novel form of glycolytic metabolism-dependent cardioprotection revealed by PKCalpha and beta inhibition. J Physiol, 597, 4481-4501.

JACKSON R, BRENNAN S, FIELDING P, SIMS MW, CHALLISS RA, ADLAM D, SQUIRE IB & RAINBOW RD 2016. Distinct and complementary roles for alpha and beta isoenzymes of PKC in mediating vasoconstrictor responses to acutely elevated glucose. Br J Pharmacol, 173, 870-87.

SIMS MW, WINTER J, BRENNAN S, NORMAN RI, NG GA, SQUIRE IB & RAINBOW RD. 2014. PKC-mediated toxicity of elevated glucose concentration on cardiomyocyte function. Am J Physiol Heart Circ Physiol, 307, H587-97.

RAINBOW RD, HARDY ME, STANDEN NB & DAVIES NW. 2006. Glucose reduces endothelin inhibition of voltage-gated potassium channels in rat arterial smooth muscle cells. J Physiol, 575, 833-44.