Rad-deletion Phenocopies Tonic Sympathetic Stimulation of the Heart

Abstract

Sympathetic stimulation modulates L-type calcium channel (LTCC) gating to contribute to increased systolic heart function. Rad is a monomeric G-protein that interacts with LTCC. Genetic deletion of Rad (Rad−/−) renders LTCC in a sympathomimetic state. The study goal was to use a clinically inspired pharmacological stress echocardiography test, including analysis of global strain, to determine whether Rad−/− confers tonic positive inotropic heart function. Sarcomere dynamics and strain showed partial parallel isoproterenol (ISO) responsiveness for wild-type (WT) and for Rad−/−. Rad−/− basal inotropy was elevated compared to WT but was less responsiveness to ISO. Rad protein levels were lower in human patients with end-stage non-ischemic heart failure. These results show that Rad reduction provides a stable inotropic response rooted in sarcomere level function. Thus, reduced Rad levels in heart failure patients may be a compensatory response to need for increased output in the setting of HF. Rad deletion suggests a future therapeutic direction for inotropic support.

Rad GTPase Deletion Attenuates Post-Ischemic Cardiac Dysfunction and Remodeling

“…Nevertheless, function in the Rad −/− mice appears to be sufficiently preserved to avoid the precipitous drop in cardiac output and blood pressure observed in WT mice ( Figure 3 ). This acute preservation of function occurs prior to scar spread and myocardial remodeling, suggesting that the improved inotropy associated with Rad deletion 12 , 27 is maintained after AMI. In WT mice after MI, loss of function results in reflexive, tonic elevation of sympathetic drive that causes pathological cardiomyocyte remodeling.…”

“…The Rad −/− heart has stable elevated function compared with WT 12 , 27 . This functional gain is preserved 24 h after LAD ligation, although there is a parallel reduction of function in both Rad −/− and MI ( Figure 2 ).…”

“…An early study of the Rad −/− mouse showed increased hypertrophy (13) ; however, it is important to note that this early work performed no functional evaluations. We have now documented stable, chronic positive inotropic function that phenocopies β-adrenergic receptor stimulation in Rad-deficient mice into aging 17 , 27 . Our studies suggest the importance of reevaluating whether Rad-increased Ca 2+ homeostasis, along with modest cardiac hypertrophy, can form a basis for future safe, stable positive inotropic therapeutic directions.…”

Molecular mechanisms and physiological relevance of RGK proteins in the heart

“…In addition, Rad null mice of advanced age (18 months) exhibited an increased rate of SR Ca 2+ uptake via SERCA2a that the authors interpreted as a contributing mechanism to the observed cardioprotective phenotype . More recent work has shown the preservation of inotropic function through more efficient sarcomeric function in Rad null mice . As Rad expression was found to be decreased in non‐ischaemic failing human myocardium by Western blot, the authors of this latter study proposed that the downregulation of Rad in the hearts of these patients was a sympathomimetic compensatory mechanism to increase cardiac output.…”

The quest to identify the mechanism underlying adrenergic regulation of cardiac Ca2+ channels

“…Rad-knockout mice display an increased maximum Ca 2+ current, and the Ca 2+ channels activate at lower voltages, mimicking the effects of βadrenergic receptor stimulation [66,67]. Other studies, however, led to expectations that Rad is not directly involved in adrenergic regulation of Ca V 1.2 since adenoviral-induced overexpression of Rad [68] and Rem [69] in cultured cardiomyocytes ablated Ca V 1.2 and attenuated adrenergic regulation.…”