title: 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.
authors: Department of Physiology, University of Kentucky College of Medicine, 800 Rose St, Lexington, KY, 40536-0298, USA.|Gill Heart Institute, University of Kentucky, Lexington, KY, USA.
authors: Bryana M
authors: BM
authors: Levitan
authors: Department of Physiology, University of Kentucky College of Medicine, 800 Rose St, Lexington, KY, 40536-0298, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.
authors: Janet R
authors: JR
authors: Manning
authors: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.
authors: Catherine N
authors: CN
authors: Withers
authors: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.
authors: Jeffrey D
authors: JD
authors: Smith
authors: Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, University of California Los Angeles, Los Angeles, CA, USA.
authors: Robin M
authors: RM
authors: Shaw
authors: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.
authors: Douglas A
authors: DA
authors: Andres
authors: Gill Heart Institute, University of Kentucky, Lexington, KY, USA.
authors: Vincent L
authors: VL
authors: Sorrell
authors: Department of Physiology, University of Kentucky College of Medicine, 800 Rose St, Lexington, KY, 40536-0298, USA. jsatin1@uky.edu.
authors: Jonathan
authors: 0000-0001-9198-8349
authors: J
authors: Satin
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016022:Case-Control Studies; D025401:Echocardiography, Stress / Q000379:methods; D017353:Gene Deletion; D005838:Genotype; D006321:Heart / Q000294:innervation*; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007545:Isoproterenol / Q000008:administration & dosage; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012518:Sarcomeres / Q000378:metabolism / Q000473:pathology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D013566:Sympathomimetics / Q000008:administration & dosage; D020257:Ventricular Remodeling; D018631:ras Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; C084355:RRAD protein, human; C490030:Rrad protein, mouse; D013566:Sympathomimetics; D018631:ras Proteins; D007545:Isoproterenol
keywords: Beta-adrenergic stimulation; Calcium; Calcium channel; Cell shortening; Echocardiography; Heart function