Existing therapies to improve heart function target -adrenergic receptor (-AR) signaling and Ca2 handling and often lead to adverse outcomes. This underscores an unmet need for positive inotropes that improve heart function without any adverse effects. The GTPase Ras associated with diabetes (RAD) regulates L-type Ca2 channel (LTCC) current (ICa,L). Global RAD-knockout mice (gRAD /) have elevated Ca2 handling and increased cardiac hypertrophy, but RAD is expressed also in noncardiac tissues, suggesting the possibility that pathological remodeling is due also to noncardiac effects. Here, we engineered a myocardial-restricted inducible RAD-knockout mouse (RAD/). Using an array of methods and techniques, including single-cell electrophysiological and calcium transient recordings, echocardiography, and radiotelemetry monitoring, we found that RAD deficiency results in a sustained increase of inotropy without structural or functional remodeling of the heart. ICa,L was significantly increased, with RAD loss conferring a -AR–modulated phenotype on basal ICa,L. Cardiomyocytes from RAD/ hearts exhibited enhanced cytosolic Ca2 handling, increased contractile function, elevated sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2a) expression, and faster lusitropy. These results argue that myocardial RAD ablation promotes a beneficial elevation in Ca2 dynamics, which would obviate a need for increased -AR signaling to improve cardiac function.
|Number of pages||15|
|Journal||Journal of Biological Chemistry|
|State||Published - Jul 12 2019|
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health Grants HL131782 (to D. A. A. and J. S.), HL11470 and HL146676 (to J. E. S.), and GM007250 and T32-HL007567 (to J. L.), American Heart Association Grant 17SDG33670578 (to S. V.), and American Heart Association Pre-doctoral Fellowship 19PRE34380909 and NIGMS T32GM118292 (to B. M. A.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Acknowledgments—We thank Wendy Katz for histology support provided by an Institutional Development Award (IDeA) from NIGMS National Institutes of Health Grant P20 GM103527. We thank Tanya Seward for surgical support for radiotelemetry in the Physiology Department core facility. The Vevo3100 was supported by The Saha Cardiovascular Research Center.
© 2019 Ahern et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology