Loss of Rad-GTPase Produces a Novel Adaptive Cardiac Phenotype Resistant to Systolic Decline with Aging
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.
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-072936; (to D. A. Andres and J. Satin), HL-074091; (to J. Satin), F32-HL-126300-01; (to J. R. Manning), and T32-HL-072743 (to C. N. Withers); University of Kentucky 2012–2013 Research Professorship (to D. A. Andres); American Heart Association Grant 14POST20460224; (to J. R. Manning); and National Science Foundation Grant DGE-1247392 (to C. N. Withers). Additionally, research reported in this publication was supported by an Institutional Development Award (IdeA) from National Institute of General Medical Sciences Grant P20-GM-103527-05.
Manning, Janet R.; Withers, Catherine N.; Levitan, Bryana; Smith, Jeffrey D.; Andres, Douglas A.; and Satin, Jonathan, "Loss of Rad-GTPase Produces a Novel Adaptive Cardiac Phenotype Resistant to Systolic Decline with Aging" (2015). Physiology Faculty Publications. 111.