Circulation Research

RES

Hrd1 and ER-Associated Protein Degradation, ERAD, Are Critical Elements of the Adaptive ER Stress Response in Cardiac Myocytes

Hrd1 and the Adaptive ER Stress Response

CIRCRES/2015/306993D

10.1161/CIRCRESAHA.115.306993 117

08/28/15

Bridges-Lyman Gemma

410-3275005

410-3279322

Bhatnagar, Aruni University of Louisville

Dr.

Christopher

Glembotski

cglembotski@mail.sdsu.edu

Dr.

San Diego State University

5500 Campanile Drive

San Diego

California

92182

UNITED STATES

619-594-2959

619-594-5676

28934

Shirin

Doroudgar

San Diego State University

shirin_doroudgar@yahoo.com

103013

Mirko

Völkers

San Diego State University

mirkovoelkers@gmx.de

103023

Donna

Thuerauf

San Diego State University

dthuerauf@mail.sdsu.edu

103024

Mohsin

Khan

Temple University School of Medicine

mohsin.khan@temple.edu

257698

Sadia

Mohsin

Temple University School of Medicine

sadia_cemb@yahoo.com

154393

Jonathan

Respress

Baylor College of Medicine

respress@bcm.edu

126705

Wei

Wang

Hebei Medical University

weiwang@hebmu.edu.cn

100579

Natalie

Gude

San Diego State University

ngude@mail.sdsu.edu

103022

Oliver

Müller

University Hospital Heidelberg

Oliver.Mueller@med.uni-heidelberg.de

121191

Xander

Wehrens

Baylor College of Medicine

wehrens@bcm.edu

21613

Mark

Sussman

San Diego State University

heartman4ever@icloud.com

11355

Christopher

Glembotski

San Diego State University

cglembotski@mail.sdsu.edu

28934

06/09/2015

06/26/2015

07/01/2015

07/02/2015

Regular Article

ERAD Hrd1 protein degradation protein folding

Rationale: Hrd1 is an endoplasmic reticulum (ER)-transmembrane E3 ubiquitin ligase that has been studied in yeast, where it contributes to ER protein quality control by ER-associated degradation (ERAD) of misfolded proteins that accumulate during ER stress. Neither Hrd1 nor ERAD have been studied in the heart, or in cardiac myocytes, where protein quality control is critical for proper heart function. Objective: The objectives of this study were to elucidate roles for Hrd1 in ER stress, ERAD, and viability in cultured cardiac myocytes and in the mouse heart, in vivo. Methods and Results: The effects of siRNA-mediated Hrd1 knockdown were examined in cultured neonatal rat ventricular myocytes. The effects of adeno-associated virus (AAV)-mediated Hrd1 knockdown and overexpression were examined in the hearts of mice subjected to pressure-overload induced pathological cardiac hypertrophy, which challenges protein-folding capacity. In cardiac myocytes, the ER stressors, thapsigargin (TG) and tunicamycin (TM) increased ERAD, as well as adaptive ER stress proteins, and minimally affected cell death. However, when Hrd1 was knocked down, TG and TM dramatically decreased ERAD, while increasing maladaptive ER stress proteins and cell death. In vivo, Hrd1 knockdown exacerbated cardiac dysfunction, and increased apoptosis and cardiac hypertrophy, while Hrd1 overexpression preserved cardiac function, and decreased apoptosis and attenuated cardiac hypertrophy in the hearts of mice subjected to pressure-overload. Conclusions: Hrd1 and ERAD are essential components of the adaptive ER stress response in cardiac myocytes. Hrd1 contributes to preserving heart structure and function in a mouse model of pathological cardiac hypertrophy.

yes

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CircRes_CIRCRES-2015-306993D_merge.pdf

CircRes_CIRCRES-2015-306993D_Thuerauf_103024_disclosure.pdf

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CircRes_CIRCRES-2015-306993D_Wang_100579_disclosure.pdf

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CircRes_CIRCRES-2015-306993D_Wehrens_21613_disclosure.pdf

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CircRes_CIRCRES-2015-306993D_Mller_121191_disclosure.pdf

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CircRes_CIRCRES-2015-306993D_Glembotski_28934_disclosure.pdf

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CircRes_CIRCRES-2015-306993D_Mohsin_154393_disclosure.pdf

CircRes_CIRCRES-2015-306993D_Mohsin_154393_copyright.pdf

CircRes_CIRCRES-2015-306993D_Sussman_11355_disclosure.pdf

CircRes_CIRCRES-2015-306993D_Sussman_11355_copyright.pdf

CircRes_CIRCRES-2015-306993D_Respress_126705_disclosure.pdf

CircRes_CIRCRES-2015-306993D_Respress_126705_copyright.pdf

CircRes_CIRCRES-2015-306993D_Gude_103022_disclosure.pdf

CircRes_CIRCRES-2015-306993D_Gude_103022_copyright.pdf

CircRes_CIRCRES-2015-306993D_Khan_257698_disclosure.pdf

CircRes_CIRCRES-2015-306993D_Khan_257698_copyright.pdf

CircRes_CIRCRES-2015-306993D_Doroudgar_103013_disclosure.pdf

CircRes_CIRCRES-2015-306993D_Doroudgar_103013_copyright.pdf

CircRes_CIRCRES-2015-306993D_Vlkers_103023_disclosure.pdf

CircRes_CIRCRES-2015-306993D_Vlkers_103023_copyright.pdf

PAP: 07/02/15 Funding: Howard Hughes Medical Institute (HHMI): No National Institutes of Health (NIH): Yes Not applicable for this manuscript: No Other: Yes Wellcome Trust: No Subject Codes: [138] Cell signaling/signal transduction [148] Heart failure - basic studies [108] Other myocardial biology gbridgeslyman