Research targets heart damage enzyme

Published On Tue 25 Nov 2014 by Roddy Isles

The workings of an enzyme which is thought to play a role in damaging heart muscle during a heart attack have been revealed for the first time by researchers at the University of Dundee.

The teams’ research into the enzyme DHHC5 raises the possibility that it might be a plausible drug target.

The results of the research, which was supported by a grant from the British Heart Foundation (BHF), are published in Proceedings of the National Academy of Sciences (PNAS), one of the world's most-cited and comprehensive multidisciplinary scientific journals.

Professor Jeremy Pearson, Associate Medical Director at the BHF, said, “The research, by showing the precise way in which the DHHC5 enzyme works, offers the potential to design urgently needed new drugs that may block its damaging effect on heart cells after a heart attack that can lead to debilitating heart failure. 

“These results are an important first step towards the goal of developing new treatments to prevent damage after a heart attack, but it will require considerably more research to understand whether their promise can be converted into clinical benefit.”

DHHC5 was already known to be essential for all sorts of biological processes, including helping to establish short term memory in the brain. It was suspected to be one of the most important controllers of injury to the muscle in the heart during a heart attack but until now it was not understood how DHHC5 worked.

Now Dr Will Fuller and colleagues in the Medical Research Institute at the University of Dundee, working with colleagues at the Universities of Edinburgh and Leeds and King’s College London, have established details of the role of DHHC5 and how it carries it out.

They found that DHHC5 has an ‘arm’ whose job it is to catch its substrates. When particular parts of this arm are removed, it no longer finds particular substrates and can’t function properly.

Dr Fuller’s team focussed on one particular substrate, phospholemman, and identified firstly how DHHC5 finds this substrate and secondly how that regulates the force of contraction by the heart muscle. During a heart attack, DHHC5 becomes too active, and this causes damage to the heart muscle.

“There are multiple implications arising from our research,” said Dr Fuller. “DHHC5 is a member of a family of enzymes which are implicated in progression of a variety of clinical conditions, including neurological diseases and cancer. So knowing more about how it works could lead to significant developments in those disease areas.

“Secondly, understanding how DHHC5 works raises the possibility that drugs may be able selectively to manipulate its activity by targeting different parts of the ‘arm’ that catches substrates.

“This means we might be able to interfere with the ‘bad’ things this enzyme does, like damaging heart muscle during a heart attack, without affecting the ‘good’ things such as establishing memories in the brain.”

A PhD studentship just awarded by the British Heart Foundation to Dr Fuller will support follow-up studies to find out more about how the ‘arm’ of DHHC5 works.

Roddy Isles
Head of Press
TEL: 01382 384910
MOBILE: 07800 581902
E-MAIL: r.isles@dundee.ac.uk