Loss of Rad-GTPase produces a novel adaptive cardiac phenotype resistant to systolic decline with aging

Janet R. Manning, Catherine N. Withers, Bryana Levitan, Jeffrey D. Smith, Douglas A. Andres, Jonathan Satin

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Rad-GTPase is a regulator of L-type calcium current (LTCC), with increased calcium current observed in Rad knockout models. While mouse models that result in elevated LTCC have been associated with heart failure, our laboratory and others observe a hypercontractile phenotype with enhanced calcium homeostasis in Rad-/-. It is currently unclear whether this observation represents an early time point in a decompensatory progression towards heart failure or whether Rad loss drives a novel phenotype with stable enhanced function. We test the hypothesis that Rad-/- drives a stable nonfailing hypercontractile phenotype in adult hearts, and we examine compensatory regulation of sarcoplasmic reticulum (SR) loading and protein changes. Heart function was measured in vivo with echocardiography. In vivo heart function was significantly improved in adult Rad-/- hearts compared with wild type. Heart wall dimensions were significantly increased, while heart size was decreased, and cardiac output was not changed. Cardiac function was maintained through 18 mo of age with no decompensation. SR releasable Ca2+ was increased in isolated Rad-/- ventricular myocytes. Higher Ca2+ load was accompanied by sarco/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) protein elevation as determined by immunoblotting and a rightward shift in the thapsigargan inhibitor-response curve. Rad-/- promotes morphological changes accompanied by a stable increase in contractility with aging and preserved cardiac output. The Rad-/- phenotype is marked by enhanced systolic and diastolic function with increased SR uptake, which is consistent with a model that does not progress into heart failure.

Original languageEnglish
Pages (from-to)H1336-H1345
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number8
StatePublished - 2015

Bibliographical note

Publisher Copyright:
© 2015 the American Physiological Society.


  • Calcium signaling
  • Cardiac hypertrophy
  • Echocardiography
  • Genetically modified mice

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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