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.
|Number of pages||13|
|Journal||Journal of Cardiovascular Translational Research|
|State||Published - Dec 1 2016|
Bibliographical noteFunding Information:
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.
© 2016, Springer Science+Business Media New York.
- Beta-adrenergic stimulation
- Calcium channel
- Cell shortening
- Heart function
ASJC Scopus subject areas
- Molecular Medicine
- Pharmaceutical Science
- Cardiology and Cardiovascular Medicine