title: Loss of Rad-GTPase produces a novel adaptive cardiac phenotype resistant to systolic decline with aging.
abstract: 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 Ca(2+) was increased in isolated Rad(-/-) ventricular myocytes. Higher Ca(2+) load was accompanied by sarco/endoplasmic reticulum Ca(2+) 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.
authors.affiliation: Department of Physiology, University of Kentucky, Lexington, Kentucky; Department of Biochemistry, University of Kentucky, Lexington, Kentucky; and.
authors.forename: Janet R
authors.initials: JR
authors.lastname: Manning
authors.affiliation: Department of Biochemistry, University of Kentucky, Lexington, Kentucky; and.
authors.forename: Catherine N
authors.initials: CN
authors.lastname: Withers
authors.affiliation: Gill Heart Institute, University of Kentucky, Lexington, Kentucky.
authors.forename: Bryana
authors.initials: B
authors.lastname: Levitan
authors.affiliation: Department of Biochemistry, University of Kentucky, Lexington, Kentucky; and.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: Department of Biochemistry, University of Kentucky, Lexington, Kentucky; and.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Andres
authors.affiliation: Department of Physiology, University of Kentucky, Lexington, Kentucky; jsatin1@uky.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Satin
mesh_terms: D000222:Adaptation, Physiological; D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020013:Calcium Signaling; D002302:Cardiac Output; D018450:Disease Progression; D005838:Genotype; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013599:Systole; D018487:Ventricular Dysfunction, Left / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D016277:Ventricular Function, Left; D018631:ras Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: C490030:Rrad protein, mouse; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D018631:ras Proteins; C506947:Atp2a2 protein, mouse
keywords: calcium signaling; cardiac hypertrophy; echocardiography; genetically modified mice