Rad-deletion Phenocopies Tonic Sympathetic Stimulation of the Heart

  • Bryana M. Levitan
  • Janet R. Manning
  • Catherine N. Withers
  • Jeffrey D. Smith
  • Robin M. Shaw
  • Douglas A. Andres
  • Vincent L. Sorrell
  • Jonathan Satin
Original Article

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.

Keywords

Calcium channel Echocardiography Calcium Cell shortening Beta-adrenergic stimulation Heart function 

Abbreviations

β-AR

Beta-adrenergic receptor

EF

Ejection fraction

ISO

Isoproterenol

LTCC

L-type calcium channel

LVEF

Left ventricular ejection fraction

LVID;d

Left ventricular inner dimension diastolic

Rad−/−

Genetic global RRAD knockout mouse

SL

Sarcomere length

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Bryana M. Levitan
    • 1
    • 2
  • Janet R. Manning
    • 1
    • 3
  • Catherine N. Withers
    • 3
  • Jeffrey D. Smith
    • 3
  • Robin M. Shaw
    • 4
  • Douglas A. Andres
    • 3
  • Vincent L. Sorrell
    • 2
  • Jonathan Satin
    • 1
  1. 1.Department of PhysiologyUniversity of Kentucky College of MedicineLexingtonUSA
  2. 2.Gill Heart InstituteUniversity of KentuckyLexingtonUSA
  3. 3.Department of Molecular and Cellular BiochemistryUniversity of KentuckyLexingtonUSA
  4. 4.Cedars-Sinai Heart Institute, Cedars-Sinai Medical CenterUniversity of California Los AngelesLos AngelesUSA

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