Modulation of cAMP microdomains to treat heart failure

The ubiquitous second messenger cAMP plays central roles in the regulation of cardiac function and diseases such as hypertrophy and heart failure. Especially the stimulation of cardiomyocyte ?-adrenoceptors leads to strong contractile response and disease progression, while other membrane receptors coupled to the stimulatory G-protein (Gs) play less prominent role. Beta-blockers are therefore central to the therapy but lead to non-cardiac side-effects which limit patient compliance. This project will test the hypothesis that cardiomyocyte-specific delivery of a dominant negative Gs mutant should provide beneficial antihypertrophic effect without systemic side-effects. This mutant will be studied in mouse diseased models and introduced into AAV for gene therapy studies.