title: Differential regulation of EHD3 in human and mammalian heart failure.
abstract: Electrical and structural remodeling during the progression of cardiovascular disease is associated with adverse outcomes subjecting affected patients to overt heart failure (HF) and/or sudden death. Dysfunction in integral membrane protein trafficking has long been linked with maladaptive electrical remodeling. However, little is known regarding the molecular identity or function of these intracellular targeting pathways in the heart. Eps15 homology domain-containing (EHD) gene products (EHD1-4) are polypeptides linked with endosomal trafficking, membrane protein recycling, and lipid homeostasis in a wide variety of cell types. EHD3 was recently established as a critical mediator of membrane protein trafficking in the heart. Here, we investigate the potential link between EHD3 function and heart disease. Using four different HF models including ischemic rat heart, pressure overloaded mouse heart, chronic pacing-induced canine heart, and non-ischemic failing human myocardium we provide the first evidence that EHD3 levels are consistently increased in HF. Notably, the expression of the Na/Ca exchanger (NCX1), targeted by EHD3 in heart is similarly elevated in HF. Finally, we identify a molecular pathway for EHD3 regulation in heart failure downstream of reactive oxygen species and angiotensin II signaling. Together, our new data identify EHD3 as a previously unrecognized component of the cardiac remodeling pathway.
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Hjalti
authors.initials: H
authors.lastname: Gudmundsson
authors.forename: Jerry
authors.initials: J
authors.lastname: Curran
authors.forename: Farshid
authors.initials: F
authors.lastname: Kashef
authors.forename: Jedidiah S
authors.initials: JS
authors.lastname: Snyder
authors.forename: Sakima A
authors.initials: SA
authors.lastname: Smith
authors.forename: Pedro
authors.initials: P
authors.lastname: Vargas-Pinto
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Bonilla
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Philip
authors.initials: P
authors.lastname: Binkley
authors.forename: Robert B
authors.initials: RB
authors.lastname: Felder
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Carnes
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D004285:Dogs; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006352:Heart Ventricles / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C406447:EHD3 protein, human; D017382:Reactive Oxygen Species; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D000804:Angiotensin II; D019255:NADPH Oxidases