Myocardial-restricted ablation of the GTPase RAD results in a pro-adaptive heart response in mice

Existing therapies to improve heart function target -adrenergic receptor (-AR) signaling and Ca² handling and often lead to adverse outcomes. This underscores an unmet need for positive inotropes that improve heart function without any adverse effects. The GTPase Ras associated with diabetes (RAD) regulates L-type Ca² channel (LTCC) current (I_Ca,L). Global RAD-knockout mice (gRAD /) have elevated Ca² handling and increased cardiac hypertrophy, but RAD is expressed also in noncardiac tissues, suggesting the possibility that pathological remodeling is due also to noncardiac effects. Here, we engineered a myocardial-restricted inducible RAD-knockout mouse (RAD/). Using an array of methods and techniques, including single-cell electrophysiological and calcium transient recordings, echocardiography, and radiotelemetry monitoring, we found that RAD deficiency results in a sustained increase of inotropy without structural or functional remodeling of the heart. I_Ca,L was significantly increased, with RAD loss conferring a -AR–modulated phenotype on basal I_Ca,L. Cardiomyocytes from RAD/ hearts exhibited enhanced cytosolic Ca² handling, increased contractile function, elevated sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2a) expression, and faster lusitropy. These results argue that myocardial RAD ablation promotes a beneficial elevation in Ca² dynamics, which would obviate a need for increased -AR signaling to improve cardiac function.