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

doi:10.1007/s12265-016-9716-y

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

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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.

Original language	English
Pages (from-to)	432-444
Number of pages	13
Journal	Journal of Cardiovascular Translational Research
Volume	9
Issue number	5-6
DOIs	https://doi.org/10.1007/s12265-016-9716-y
State	Published - Dec 1 2016

Bibliographical note

Publisher Copyright:
© 2016, Springer Science+Business Media New York.

Funding

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. 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.

Funders	Funder number
DECA/NHLBI/NIH	HL072936, HL074091, R01 HL094414, 16GRNT27790094
National Science Foundation Arctic Social Science Program	DGE-1247392
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)	R01HL094414
National Institute of General Medical Sciences COBRE	8 P20 GM103527-05
American the American Heart Association	T32-HL072743, AHA14POST20460224, NIHF32HL126300
Saha Cardiovascular Research Center, University of Kentucky

Keywords

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

ASJC Scopus subject areas

Molecular Medicine
Genetics
Pharmaceutical Science
Cardiology and Cardiovascular Medicine
Genetics(clinical)

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10.1007/s12265-016-9716-y

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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.",

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AU - Satin, Jonathan

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Rad-deletion Phenocopies Tonic Sympathetic Stimulation of the Heart

Abstract

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Funding

Keywords

ASJC Scopus subject areas

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