Understanding how PDE3A proteins function in the heart could lead to new treatments for heart failure

Phosphodiesterase 3 isoforms and beta-adrenergic control of cardiac myocyte function

Professor Manuela Zaccolo is studying heart failure, where the heart is unable to pump hard enough to deliver enough blood around the body and for which there is currently no cure. Some of the drugs used to treat heart failure work by blocking an enzyme called PDE3A. Although PDE3A inhibitors improve heart function in the short term, they are used only in acute heart failure as if used long term they increase a person’s risk of death. We don’t really understand exactly how these drugs work and what leads to these positive or negative effects. There are three different types of PDE3A, which are active in different parts of the cell and control different processes. Professor Zaccolo believes that these different types of PDE3A explain the positive and negative effects of PDE3A inhibitors used to treat heart failure. In this project, Professor Zaccolo is investigating what each different PDE3A protein does in healthy hearts and in hearts where the muscle has thickened (cardiac hypertrophy), using a combination of laboratory approaches. The team will work out how blocking PDE3A enzymes is bad for the heart and will design ways to selectively boost the good effects, aiming to avoid the negative long term effects. Understanding more about the molecules involved in heart failure could reveal ways to develop new drugs to treat the condition.