title: Differential roles of caveolin-1 in ouabain-induced Na+/K+-ATPase cardiac signaling and contractility.
abstract: Binding of ouabain to cardiac Na+/K+-ATPase initiates cell signaling and causes contractility in cardiomyocytes. It is widely accepted that caveolins, structural proteins of caveolae, have been implicated in signal transduction. It is known that caveolae play a role in Na+/K+-ATPase functions. Regulation of caveolin-1 in ouabain-mediated cardiac signaling and contractility has never been reported. The aim of this study is to compare ouabain-induced cardiac signaling and contractility in wild-type (WT) and caveolin-1 knockout (cav-1 KO) mice. In contrast with WT cardiomyocytes, ouabain-induced signaling e.g., activation of phosphoinositide 3-kinase-α/Akt and extracellular signal-regulated kinases (ERK)1/2, and hypertrophic growth were significantly reduced in cav-1 KO cardiomyocytes. Interactions of the Na+/K+-ATPase α1-subunit with caveolin-3 and the Na+/K+-ATPase α1-subunit with PI3K-α were also decreased in cav-1 KO cardiomyocytes. The results from cav-1 KO mouse embryonic fibroblasts also proved that cav-1 significantly attenuated ouabain-induced ERK1/2 activation without alteration in protein and cholesterol distribution in caveolae/lipid rafts. Intriguingly, the effect of ouabain induced positive inotropy in vivo (via transient infusion of ouabain, 0.48 nmol/g body wt) was not attenuated in cav-1 KO mice. Furthermore, ouabain (1-100 μM) induced dose-dependent contractility in isolated working hearts from WT and cav-1 KO mice. The effects of ouabain on contractility between WT and cav-1 KO mice were not significantly different. These results demonstrated differential roles of cav-1 in the regulation of ouabain signaling and contractility. Signaling by ouabain, in contrast to contractility, may be a redundant property of Na+/K+-ATPase.
authors: Department of Biochemistry and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio; Pediatrics Department of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei, China.
authors: Yan
authors: Y
authors: Bai
authors: Department of Biochemistry and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio.
authors: Jian
authors: J
authors: Wu
authors: Department of Biochemistry and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio; State Key Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, Hefei, Anhui, China; and.
authors: Daxiang
authors: D
authors: Li
authors: Center for Hypertension and Personalized Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio.
authors: Eric E
authors: EE
authors: Morgan
authors: Department of Pharmacology, Physiology and Toxicology, JCE School of Medicine, Marshall University, Huntington, West Virginia.
authors: Jiang
authors: J
authors: Liu
authors: Department of Physiology and Pharmacology, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio.
authors: Xiaochen
authors: X
authors: Zhao
authors: Department of Biochemistry and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio.
authors: Aaron
authors: A
authors: Walsh
authors: Department of Physiology and Pharmacology, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio.
authors: Jagannath
authors: J
authors: Saikumar
authors: Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio.
authors: Jodi
authors: J
authors: Tinkel
authors: Department of Physiology and Pharmacology, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio; Center for Hypertension and Personalized Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio.
authors: Bina
authors: B
authors: Joe
authors: Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio.
authors: Rajesh
authors: R
authors: Gupta
authors: Department of Biochemistry and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio; Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio; Center for Hypertension and Personalized Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio; Lijun.liu@utoledo.edu.
authors: Lijun
authors: L
authors: Liu
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
chemical_list: D051242:Caveolin 1; D002784:Cholesterol; D010042:Ouabain; D019869:Phosphatidylinositol 3-Kinases; D000254:Sodium-Potassium-Exchanging ATPase; C495541:Cav1 protein, mouse
keywords: Na+/K+-ATPase; caveolin-1; contractility; ouabain; signaling