Cardiac Functional and Metabolic Consequences of Ghrelin Agonism

Summary

Ghrelin is a 28-amino acid peptide secreted by the gastric submucosal layer. Ghrelin receptors are widely expressed, including in the CNS, GI tract, vasculature and myocardium. Potential cardioprotective effects have been proposed. Direct mechanisms include a positive effect on contractile function and inhibition of collagen synthesis to prevent fibrosis. Indirectly, ghrelin is proposed to activate parasympathetic tone and inhibit sympathetic nerve activity.

Project aims

This project will investigate mechanisms of ghrelin agonism, focusing on myocardial function, metabolism and energetics. Studies will use control rats and a model of heart failure with preserved ejection fraction (HFpEF) based on high-fat feeding alongside the nitric oxide synthase inhibitor, L-NAME (HFD+L-NAME), using novel, half-life extended, long-acting ghrelin agonists. 

Acute effects will be investigated in isolated, Langendorff-perfused hearts. Cardiac function will be assessed at baseline and following ghrelin agonist administration, including systolic/diastolic function, heart rate and developed pressure. Separately, cardioprotective effects will be measured in hearts subjected to low-flow ischaemia/reperfusion, with functional recovery and mitochondrial respiration measured post-ischaemia. 

These studies will be complemented by in vivo analysis. Control and HFD+L-NAME rats will be treated with a stabilized ghrelin agonist, cardiac function assessed in vivo by echocardiography and ex vivo by Langendorff perfusion. Fibrosis will be quantified by histology, mitochondrial respiration will be analysed and comprehensive metabolomic and lipidomic profiling carried out. 

Further mechanistic work may be carried out in H9C2 cardiomyocytes. Overall, this project will provide new evidence for the mechanistic basis of ghrelin action, and indicate any therapeutic potential in the context of HFpEF

Contact details

Andrew Murray - ajm267@cam.ac.uk

Opportunities

This project is open to applicants who want to do a:

• PhD