Remote ischaemic conditioning: a novel approach to reduce hypertrophy?

Cardiac hypertrophy is a significant clinical issue. Enlargement of the heart caused by hypertension, injury or other disease, can cause increased muscle mass, increased fibrous tissue and lead to poor function, stiffer hearts and ultimately heart failure. The most common cause of hypertrophy within the heart is hypertension, where an increased pre- and afterload on the heart causes enlargement to compensate for the increased pressure. Ischaemia, cause by coronary artery disease, or by coronary ischaemia, is also a significant issue. Recently, we have demonstrated that remote ischaemic conditioning, where a blood pressure cuff is inflated to above systolic pressure for 5 minutes to cause limb ischaemia, followed by 5 minutes of reperfusion, and this process repeated 4 times, releases a “humoral factor” into the blood that acts to protect the heart from prolonged ischaemia, but also prevents hypertrophy.

In this study, remoted conditioned serum from human volunteers will be used to assess the anti-hypertrophic properties in rat cardiomyocytes. We have established models of hypertrophy using angiotensin II, endothelin I and Phenylephrine along with a model of continuous stretch that can induce hypertrophy in isolated cells. In all cases, the remote conditioned serum can prevent this hypertrophy. Using pharmacological modulators of known protective pathways, we will assess the mechanisms by which this anti-hypertrophic effect is occurring. For example, we believe that the humoral factor responsible may involve an opioid-type compound, and so we will use selective receptor blockers to assess the contribution of opioid receptors to this anti-hypertrophic effect.

Furthermore, ischaemic preconditioning of the heart is able to prevent such hypertrophy from occurring. Moreover, the superfusate collected from the heart during the ischaemic preconditioning protocol is able to protect non-ischaemic preconditioned cells from hypertrophy, suggesting that the heart itself is producing a similar humoral factor.

In this study, the student will use imaging of freshly isolated cardiac cells to assess changes in hypertrophy with different induction protocols, metabolic assessment of control vs hypertrophied cells using seahorse respirometry and the effects that remote conditioned serum has on the metabolic profile of control and hypertrophied cells, together with pharmacological profiling of the hypertrophic response to establish how the serum is protecting against hypertrophy. Finally, using Mass Spec, NMR or Elisa methods, the student will assess the serum for compounds that are identified as potentially having an anti-hypertrophic effect on the cardiac tissue.

The development of heart failure is thought to involve the activation of a number of complex signalling pathways, including Akt and ERK triggered by matrix metalloproteinases. Further evidence suggests that Wnt signalling may have a role in promoting inflammation and fibrosis in heart failure, with further studies suggesting a role for hyperglycaemia-linked PKCβ signalling. Using a human iPSC-cardiomyocyte model, the effects of hypertrophic stimuli on these pathways, and the effectiveness of the cardioprotective perfusate or serum, will be assessed.

This project will be the first to investigate the anti-hypertrophic effects of remote ischaemic conditioning and will work towards identifying factor(s) released by muscles during an ischaemic conditioning responses to have these protective effects. The student will also investigate whether direct modulation of signalling pathways, inhibition or activation of MMP’s, or inhibition of PKCβ may have an anti-hypertrophic effect.

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. All techniques are established in the laboratory groups of the supervisory team.

Applicant Information

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.

Application is via CV and cover letter to the Project Supervisor email [email protected]