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: Hjalti Gudmundsson, Jerry Curran, Farshid Kashef, Jedidiah S Snyder, Sakima A Smith, Pedro Vargas-Pinto, Ingrid M Bonilla, Robert M Weiss, Mark E Anderson, Philip Binkley, Robert B Felder, Cynthia A Carnes, Hamid Band, Thomas J Hund, Peter J Mohler
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 52 Issue 5 Pg. 1183-90 (May 2012) ISSN: 1095-8584 [Electronic] England
• PMID: 22406195 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Carrier Proteins
• EHD3 protein, human
• Reactive Oxygen Species
• Sodium-Calcium Exchanger
• sodium-calcium exchanger 1
• Angiotensin II
• NADPH Oxidases

Topics

• Angiotensin II (metabolism)
• Animals
• Carrier Proteins (genetics, metabolism)
• Case-Control Studies
• Cells, Cultured
• Dogs
• Gene Expression Regulation
• Heart Failure (enzymology, metabolism, pathology)
• Heart Ventricles (enzymology, metabolism, pathology)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Myocytes, Cardiac (enzymology, metabolism)
• NADPH Oxidases (metabolism)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Sodium-Calcium Exchanger (metabolism)