New drugs to break the cycle of heart scarring

Breaking the cycle of cardiac fibrosis: Harnessing the anti-fibrotic effects of cAMP

The build-up of scar tissue in the heart (fibrosis) is a key process that contributes to heart failure. It is caused by an increased number of cells called fibroblasts, which lay together to form scar tissue. The result is that the heart wall stiffens, making it harder for the heart to pump. In turn, the increased stiffness causes fibroblast cells to change the make-up of their ‘skeleton’, creating a cycle of continuous scarring. This project aims to test whether increased stiffness of the heart chamber walls switches on genes that promote the growth of fibroblasts and other scar-promoting processes. They will focus on two sets of molecules that work together called MKL-SRF and YAP/TAZ-TEAD. Previous research suggests that these molecules can ‘sense’ the stiffness of their surroundings and switch on genes involved in cell growth. There is already a potential drug that can block MKL1-SRF and Dr Bond’s previous BHF-funded research helped identify a new drug that can also block YAP/TAZ-TEAD. This project will test for the first time whether these drugs can break the vicious cycle of heart scarring in zebrafish. If they do have anti-scarring effects, it will lay the foundations for future testing of these drugs in larger animals and ultimately in clinical trials.