Targeting of a PKA-AKAP18d-phospholamban signalling complex in the heart as therapy for chronic heart failure

The adrenalin-beta-adrenergic receptor-cAMP-protein kinase A signalling pathway regulates heart rate and contractility. Although changes in cardiac myocyte contractility either cause or are associated with cardiovascular disease, surprisingly few drugs ar e available that modulate the cardiac myocyte cAMP system. Already existing beta-blocking agents reduce cAMP levels only by 50%. New compounds that interfere with the pathway at other levels may provide a new tool for treatment of heart failure to used al one or together with beta-blockers and may serve to make the therapy more potent and/or more targeted avoiding side effects. We have identified a supramolecular complex of the Ca2+ ATPase Serca2, its regulator phospholamban (PLB), protein kinase A and the A kinase anchoring protein AKAP18d that controls the adrenergic effect on Ca2+ reabsorbtion and the heart relaxation which is rate limiting for an increased heart rate. Targeting the compartmentalisation of this cAMP signalling complex by specific molecu lar disruptors interferes with adrenalin-induced PKA phosphorylation of PLB, prevents activation of Serca2 and thereby increased energy consumption. This blocking effect is believed to be cardio-protective in the post-infarction heart and to protect again st chronic heart failure. Here we wish to test a molecular disruptor peptidomimetic in whole perfused hearts and living animals with induced post-infarction heart failure to get proof of principle and verify the product. Furthermore, we wish to screen for small molecular compounds that hit on the same drug target.