Abstract 17994: Rad Gtpase Depletion is a Novel Positive Inotrope Without Pathological Signaling
Rationale: The small GTPase Rad is a negative regulator of voltage-dependent L-type calcium channel (LTCC) current (ICaL); however, the effects of Rad ablation on cardiomyocyte function and calcium homeostasis are unknown. Increased ICa,L may have dual effects , inducing transcriptional regulation in addition to positive inotropism. Alternatively, Rad as a member of the LTCC complex may restrict effects to contractile function only.
Objective: This study tests the hypothesis that Rad-depletion causes positive inotropic effects without inducing pathological transcriptional signaling.
Methods and Results: Ventricular myocytes from adult Rad-/- mice were isolated and evaluated for ICa,L and action potentials by patch clamp recordings, as well as calcium transients, and sarcomere shortening. Maximum ICaL is elevated in Rad-/-, decay kinetics are faster, and ICa,L activated at lower voltages thus mimicking effects of beta-adrenergic receptor (β-AR) stimulation. Diastolic and systolic calcium are elevated in Rad-/-, and sarcomere shortening is enhanced, particularly at lower pacing frequencies. Consequentially frequency-dependence of calcium transients is reduced in Rad-/-, and the frequency dependence of relaxation is also significantly blunted. In isolated ex vivo working hearts similar results were obtained, chiefly, contractility (+dP/dt) was elevated at baseline and was less responsive to acute β-AR stimulation. In single cells, at lower infra-physiological frequencies, non-stimulated CaMKII-sensitive calcium release is observed. Remarkably, Rad-/- hearts did not show pathological hypertrophic growth despite elevated levels of diastolic calcium.
Conclusions: This study demonstrates that the depletion of Rad GTPase parallels β-AR agonism, remarkably without stimulating pathological cardiac hypertrophy. Thus, Rad GTPase is a novel potential therapeutic target for calcium homeostasis-driven positive inotropic support of the heart.
- © 2013 by American Heart Association, Inc.