Die Rolle der Phosphodiesterase 2 im Herzen

Heart failure is a worldwide health issue with high morbidity and mortality rates and always a poor prognostic outlook. A characteristic element of the molecular driven structural transformation, which precedes the terminal failure, is on one hand the reduction of the beta-adrenergic signal molecule cyclic adenosine monophosphate (cAMP), caused by a desensitization process, and on the other hand the increase of cyclic guanosine monophosphate (cGMP), triggered from natriuretic peptides (NP) and nitrogen monoxide (NO). Whereas high cAMP levels are known to be detrimental to the heart, cGMP-dependent signal cascades are seen as heart protective. Amplitude, localization and half life of both signal molecules are regulated by specific enzymes, called Phosphodiesterases (PDE). PDE2 is the only known isoform in this PDE superfamily that gets activated from cGMP and then degrades cAMP at a higher rate and is therefore a centerpiece of a negative crosstalk between both signal pathways. PDE2 is found to be upregulated in human and experimental heart failure and may therefore be part of the beta-adrenergic deactivation process. In the context of this thesis we therefore had a closer look at the pathophysiological role of PDE2 in the heart. It was shown, PDE2 is expressed in cardiac myocytes as well in cardiac fibroblasts. In cardiac fibroblasts cAMP/cGMP signaling is inhibiting fibroblast (CF) transformation into myofibroblasts (MyoCF), a cellular phenotype that is related to the fibrotic remodeling of the diseased heart. In CF, a PDE2 overexpression caused a decrease of basal b2-adrenergic induced cAMP synthesis and was sufficient to induce the MyoCF transformation, even in the absence of exogenic, pro-fibrotic stimuli. In accordance, functional analysis of engineered connective tissue (ECT) of PDE2 overexpressing CF showed an increase in tissue stiffness. No PDE2 effect on basal or atrial NP induced cGMP was found, and PDE2 reduced only partially the NO-induced accumulation of cGMP. Interestingly, both stimuli are able to block the PDE2-induced CF transformation despite low cAMP levels. Therefore, there could be a redundancy of both, normally contrary, signal pathways. To investigate the role of PDE2 in cardiac myocytes, a transgenic (TG) mouse model with heart specific PDE2 overexpression was used. Basal characterization showed a lower heart rate (HR) and compensatory increased contractile force, and a reduced maximal response of HR after acute beta-adrenergic stimulation. On the molecular level, this phenotype showed a reduced phosphorylation of beta-adrenergic targets, like Troponin I, Phospholamban and Ryanodine receptor 2. Long time studies were able to prove, that there are no pathological consequences from a PDE2 overexpression, but rather an increased lifespan. Initial studies with the heart insufficiency model transverse aortic constriction (TAC) showed a robust decreased heart rate and reduced wall thickness, albeit similar reduction in cardiac contractile force. Despite these clear findings and new insights in the diverse role of PDE2 in the heart, it is still not fully elucidated weather an additional activation of PDE2 is able to decelerate or prevent the progression of heart failure by intracellular beta-adrenergic blockade. Subsequent studies, such as an acute induced activation or deactivation in experimental heart failure models, could pave the way for clinical applications for therapeutic modulation of this promising target.