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


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.


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



Beta-adrenergic receptor


Ejection fraction




L-type calcium channel


Left ventricular ejection fraction


Left ventricular inner dimension diastolic


Genetic global RRAD knockout mouse


Sarcomere length



We thank technical support from F. Weston Dicken (animal colony management) and Wassim Basheer (human sample preparation). We also thank Dr. Steven Leung (U. Kentucky) for critically reading the manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare they have no competing interests.

Ethical Approval

Animal studies: All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the appropriate institutional committees.

Human studies: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.

Sources of Funding

National Institutes of Health, National Heart, Lung, and Blood Institute (NIH-NHLBI) HL072936 (DAA & JS), HL074091 (JS); AHA 16GRNT27790094 (JS); NIH R01 HL094414 (RMS); American Heart Association, AHA14POST20460224 (JRM) and NIHF32HL126300 (JRM). NIH T32-HL072743 and National Science Foundation DGE-1247392 (CNW). Research reported in this publication was supported by an Institutional Development Award (IdeA) from the National Institute of General Medical Sciences of the NIH under grant number 8 P20 GM103527-05. The Vevo2100 was generously supported by the Saha Cardiovascular Research Center, University of Kentucky.


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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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