title: Attenuation of the unfolded protein response and endoplasmic reticulum stress after mechanical unloading in dilated cardiomyopathy.
abstract: Abnormal intracellular calcium (Ca(2+)) handling can trigger endoplasmic reticulum (ER) stress, leading to activation of the unfolded protein response (UPR) in an attempt to prevent cell death. Mechanical unloading with a left ventricular assist device (LVAD) relieves pressure-volume overload and promotes reverse remodeling of the failing myocardium. We hypothesized that mechanical unloading would alter the UPR in patients with advanced heart failure (HF). UPR was analyzed in paired myocardial tissue from 10 patients with dilated cardiomyopathy obtained during LVAD implantation and explantation. Samples from healthy hearts served as controls. Markers of UPR [binding immunoglobulin protein (BiP), phosphorylated (P-) eukaryotic initiation factor (eIF2α), and X-box binding protein (XBP1)] were significantly increased in HF, whereas LVAD support significantly decreased BiP, P-eIF2α, and XBP1s levels. Apoptosis as reflected by C/EBP homologous protein and DNA damage were also significantly reduced after LVAD support. Improvement in left ventricular dimensions positively correlated with P-eIF2α/eIF2α and apoptosis level recovery. Furthermore, significant dysregulation of calcium-handling proteins [P-ryanodine receptor, Ca(2+) storing protein calsequestrin, Na(+)-Ca(2+) exchanger, sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA2a), ER chaperone protein calreticulin] was normalized after LVAD support. Reduced ER Ca(2+) content as a causative mechanism for UPR was confirmed using AC16 cells treated with a calcium ionophore (A23187) and SERCA2a inhibitor (thapsigargin). UPR activation and apoptosis are reduced after mechanical unloading, which may be mediated by the improvement of Ca(2+) handling in patients with advanced HF. These changes may impact the potential for myocardial recovery.
authors.affiliation: Division of Cardiothoracic Surgery, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York;
authors.forename: Estibaliz
authors.initials: E
authors.lastname: Castillero
authors.affiliation: Division of Cardiothoracic Surgery, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York;
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Akashi
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania;
authors.forename: Klara
authors.initials: K
authors.lastname: Pendrak
authors.affiliation: Division of Cardiothoracic Surgery, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York;
authors.forename: Halit
authors.initials: H
authors.lastname: Yerebakan
authors.affiliation: Division of Cardiothoracic Surgery, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York;
authors.forename: Marc
authors.initials: M
authors.lastname: Najjar
authors.affiliation: Division of Cardiothoracic Surgery, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York;
authors.forename: Catherine
authors.initials: C
authors.lastname: Wang
authors.affiliation: Division of Cardiothoracic Surgery, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York;
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Naka
authors.affiliation: Division of Cardiology, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York; and.
authors.forename: Donna
authors.initials: D
authors.lastname: Mancini
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania;
authors.forename: H Lee
authors.initials: HL
authors.lastname: Sweeney
authors.affiliation: Department of Anesthesiology, Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, New York, New York.
authors.forename: Jeanine
authors.initials: J
authors.lastname: D Armiento
authors.affiliation: Division of Cardiology, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York; and.
authors.forename: Ziad A
authors.initials: ZA
authors.lastname: Ali
authors.affiliation: Division of Cardiology, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York; and.
authors.forename: P Christian
authors.initials: PC
authors.lastname: Schulze
authors.affiliation: Division of Cardiothoracic Surgery, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York; ig2006@cumc.columbia.edu.
authors.forename: Isaac
authors.initials: I
authors.lastname: George
mesh_terms: D017209:Apoptosis; D037282:Calreticulin / Q000235:genetics / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery; D016022:Case-Control Studies; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008875:Middle Aged; D000071701:Regulatory Factor X Transcription Factors; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D037282:Calreticulin; D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D019837:Ryanodine Receptor Calcium Release Channel; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D019892:eIF-2 Kinase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: endoplasmic reticulum stress; unfolded protein response; ventricular assist device