Myocardial-restricted ablation of the GTPase RAD results in a pro-adaptive heart response in mice

Brooke M. Ahern, Bryana M. Levitan, Sudhakar Veeranki, Mihir Shah, Nemat Ali, Andrea Sebastian, Wen Su, Ming C. Gong, Jiayang Li, Julian E. Stelzer, Douglas A. Andres, Jonathan Satin

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)10913-10927
Number of pages15
JournalJournal of Biological Chemistry
Volume294
Issue number28
DOIs
StatePublished - Jul 12 2019

Bibliographical note

Publisher Copyright:
© 2019 Ahern et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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