ArticleCirculation research2015
Hrd1 and ER-Associated Protein Degradation, ERAD, are Critical Elements of the Adaptive ER Stress Response in Cardiac Myocytes.
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85 citing papers in PubMed.
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- A tetracycline-inducible Split TurboID system for specific biotinylation and identification of nuclear proteins from HEK293T cells.Turkish journal of biology = Turk biyoloji dergisi · 2025Article
- HRD1 reduction promotes cholesterol-induced vascular smooth muscle cell phenotypic change via endoplasmic reticulum stress.Molecular and cellular biochemistry · 2024Article
- Review
- Regulated Cell Death Pathways in Pathological Cardiac Hypertrophy.Reviews in cardiovascular medicine · 2024Review
- Promotion of endoplasmic reticulum retrotranslocation by overexpression of E3 ubiquitin-protein ligase synoviolin 1 reduces endoplasmic reticulum stress and preserves cone photoreceptors in cyclic nucleotide-gated channel deficiency.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2024Article
- Endoplasmic reticulum stress in diseases.MedComm · 2024Review
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- Human neural stem cell secretome relieves endoplasmic reticulum stress-induced apoptosis and improves neuronal functions after traumatic brain injury in a rat model.Journal of molecular histology · 2024Article
25 more citing papers are in PubMed but not listed here.
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12 authors.
Shirin DoroudgarFrom the San Diego State University Heart Institute and the Department of Biology, San Diego State University, CA (S.D., M.V., D.J.T., M.K., S.M., N.G., M.A.S., C.C.G.); Department of Cardiology, University of Heidelberg, Heidelberg, Germany (M.V.); DZKH (German Centre for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Heidelberg, Germany (M.V.); Department of Internal Medicine III (O.J.M.), University of Heidelberg, Heidelberg, Germany; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (M.K., S.M.); and Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (J.L.R., W.W., X.H.T.W.).
Mirko VölkersFrom the San Diego State University Heart Institute and the Department of Biology, San Diego State University, CA (S.D., M.V., D.J.T., M.K., S.M., N.G., M.A.S., C.C.G.); Department of Cardiology, University of Heidelberg, Heidelberg, Germany (M.V.); DZKH (German Centre for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Heidelberg, Germany (M.V.); Department of Internal Medicine III (O.J.M.), University of Heidelberg, Heidelberg, Germany; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (M.K., S.M.); and Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (J.L.R., W.W., X.H.T.W.).
Donna J ThueraufFrom the San Diego State University Heart Institute and the Department of Biology, San Diego State University, CA (S.D., M.V., D.J.T., M.K., S.M., N.G., M.A.S., C.C.G.); Department of Cardiology, University of Heidelberg, Heidelberg, Germany (M.V.); DZKH (German Centre for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Heidelberg, Germany (M.V.); Department of Internal Medicine III (O.J.M.), University of Heidelberg, Heidelberg, Germany; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (M.K., S.M.); and Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (J.L.R., W.W., X.H.T.W.).
Mohsin KhanFrom the San Diego State University Heart Institute and the Department of Biology, San Diego State University, CA (S.D., M.V., D.J.T., M.K., S.M., N.G., M.A.S., C.C.G.); Department of Cardiology, University of Heidelberg, Heidelberg, Germany (M.V.); DZKH (German Centre for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Heidelberg, Germany (M.V.); Department of Internal Medicine III (O.J.M.), University of Heidelberg, Heidelberg, Germany; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (M.K., S.M.); and Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (J.L.R., W.W., X.H.T.W.).
Sadia MohsinFrom the San Diego State University Heart Institute and the Department of Biology, San Diego State University, CA (S.D., M.V., D.J.T., M.K., S.M., N.G., M.A.S., C.C.G.); Department of Cardiology, University of Heidelberg, Heidelberg, Germany (M.V.); DZKH (German Centre for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Heidelberg, Germany (M.V.); Department of Internal Medicine III (O.J.M.), University of Heidelberg, Heidelberg, Germany; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (M.K., S.M.); and Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (J.L.R., W.W., X.H.T.W.).
Jonathan L RespressFrom the San Diego State University Heart Institute and the Department of Biology, San Diego State University, CA (S.D., M.V., D.J.T., M.K., S.M., N.G., M.A.S., C.C.G.); Department of Cardiology, University of Heidelberg, Heidelberg, Germany (M.V.); DZKH (German Centre for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Heidelberg, Germany (M.V.); Department of Internal Medicine III (O.J.M.), University of Heidelberg, Heidelberg, Germany; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (M.K., S.M.); and Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (J.L.R., W.W., X.H.T.W.).
Wei WangFrom the San Diego State University Heart Institute and the Department of Biology, San Diego State University, CA (S.D., M.V., D.J.T., M.K., S.M., N.G., M.A.S., C.C.G.); Department of Cardiology, University of Heidelberg, Heidelberg, Germany (M.V.); DZKH (German Centre for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Heidelberg, Germany (M.V.); Department of Internal Medicine III (O.J.M.), University of Heidelberg, Heidelberg, Germany; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (M.K., S.M.); and Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (J.L.R., W.W., X.H.T.W.).
Natalie GudeFrom the San Diego State University Heart Institute and the Department of Biology, San Diego State University, CA (S.D., M.V., D.J.T., M.K., S.M., N.G., M.A.S., C.C.G.); Department of Cardiology, University of Heidelberg, Heidelberg, Germany (M.V.); DZKH (German Centre for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Heidelberg, Germany (M.V.); Department of Internal Medicine III (O.J.M.), University of Heidelberg, Heidelberg, Germany; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (M.K., S.M.); and Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (J.L.R., W.W., X.H.T.W.).
Oliver J MüllerFrom the San Diego State University Heart Institute and the Department of Biology, San Diego State University, CA (S.D., M.V., D.J.T., M.K., S.M., N.G., M.A.S., C.C.G.); Department of Cardiology, University of Heidelberg, Heidelberg, Germany (M.V.); DZKH (German Centre for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Heidelberg, Germany (M.V.); Department of Internal Medicine III (O.J.M.), University of Heidelberg, Heidelberg, Germany; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (M.K., S.M.); and Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (J.L.R., W.W., X.H.T.W.).
Xander H T WehrensFrom the San Diego State University Heart Institute and the Department of Biology, San Diego State University, CA (S.D., M.V., D.J.T., M.K., S.M., N.G., M.A.S., C.C.G.); Department of Cardiology, University of Heidelberg, Heidelberg, Germany (M.V.); DZKH (German Centre for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Heidelberg, Germany (M.V.); Department of Internal Medicine III (O.J.M.), University of Heidelberg, Heidelberg, Germany; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (M.K., S.M.); and Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (J.L.R., W.W., X.H.T.W.).
Mark A SussmanFrom the San Diego State University Heart Institute and the Department of Biology, San Diego State University, CA (S.D., M.V., D.J.T., M.K., S.M., N.G., M.A.S., C.C.G.); Department of Cardiology, University of Heidelberg, Heidelberg, Germany (M.V.); DZKH (German Centre for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Heidelberg, Germany (M.V.); Department of Internal Medicine III (O.J.M.), University of Heidelberg, Heidelberg, Germany; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (M.K., S.M.); and Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (J.L.R., W.W., X.H.T.W.).
Christopher C GlembotskiFrom the San Diego State University Heart Institute and the Department of Biology, San Diego State University, CA (S.D., M.V., D.J.T., M.K., S.M., N.G., M.A.S., C.C.G.); Department of Cardiology, University of Heidelberg, Heidelberg, Germany (M.V.); DZKH (German Centre for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Heidelberg, Germany (M.V.); Department of Internal Medicine III (O.J.M.), University of Heidelberg, Heidelberg, Germany; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (M.K., S.M.); and Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (J.L.R., W.W., X.H.T.W.). cglembotski@mail.sdsu.edu.
Funding
Surgery, Physiology and ImmunohistopathologyP01HL085577 · NHLBI · SAN DIEGO STATE UNIVERSITY · PI SUSSMAN, MARK ALAN · 2006 to 2017
$18.4MInitiative for Maximizing Student Development (IMSD) ProgramR25GM056929 · NIGMS · BAYLOR COLLEGE OF MEDICINE · PI PEREIRA, FRED A · 1998 to 2023
$12.4MMolecular Physiology of the Cardiovascular SystemT32HL007676 · NHLBI · BAYLOR COLLEGE OF MEDICINE · PI HAMILTON, SUSAN L · 1989 to 2020
$7.9MRyanodine receptor regulation in post-operative atrial fibrillationR01HL089598 · NHLBI · BAYLOR COLLEGE OF MEDICINE · PI WEHRENS, XANDER H.T. · 2007 to 2022
$6.5MRegulation of Signal Transduction to Treat Heart FailureR01HL067245 · NHLBI · SAN DIEGO STATE UNIVERSITY · PI SUSSMAN, MARK ALAN · 2001 to 2021
$6.0MStem Cell Signaling in the Pathologically Challenged MyocardiumR37HL091102 · NHLBI · SAN DIEGO STATE UNIVERSITY · PI SUSSMAN, MARK ALAN · 2008 to 2017
$3.8MRegulation of Sarcoplasmic Reticulum Calcium Release in Heart FailureR01HL091947 · NHLBI · BAYLOR COLLEGE OF MEDICINE · PI WEHRENS, XANDER H.T. · 2009 to 2019
$3.2MRole of Unfolded Protein Response in Cardiac ProtectionR01HL075573 · NHLBI · SAN DIEGO STATE UNIVERSITY · PI GLEMBOTSKI, CHRIS · 2004 to 2011
$3.0MDetermining the Role of Junctophilin-2 in Cardiac DiseaseR01HL117641 · NHLBI · BAYLOR COLLEGE OF MEDICINE · PI WEHRENS, XANDER H.T. · 2014 to 2017
$2.3MBeta-adrenergic signaling: double edged sword of myocardial repairR01HL117163 · NHLBI · SAN DIEGO STATE UNIVERSITY · PI SUSSMAN, MARK ALAN · 2013 to 2017
$1.9MAntagonism of myocardial aging and senescence with Pim-1 kinaseR01HL105759 · NHLBI · SAN DIEGO STATE UNIVERSITY · PI SUSSMAN, MARK ALAN · 2011 to 2015
$1.8MRole of the SR/ER E3 Ubiquitin Ligase Synoviolin 1 in Cardiac HypertrophyR01HL127439 · NHLBI · SAN DIEGO STATE UNIVERSITY · PI GLEMBOTSKI, CHRIS · 2015 to 2018
$1.7MNHLBI NIH HHS P01 HL085577NHLBI NIH HHS P01 HL 08577NHLBI NIH HHS R01 HL067245NHLBI NIH HHS R01 HL075573NHLBI NIH HHS R01 HL089598NHLBI NIH HHS R01 HL091947NHLBI NIH HHS R01 HL104535NHLBI NIH HHS R01 HL105759NHLBI NIH HHS R01 HL113647NHLBI NIH HHS R01 HL113656NHLBI NIH HHS R01 HL117163NHLBI NIH HHS R01 HL117641NHLBI NIH HHS R01 HL127439NHLBI NIH HHS R01 HL75573NHLBI NIH HHS R37 HL091102NHLBI NIH HHS R41 HL129570NHLBI NIH HHS R56 HL121539NHLBI NIH HHS T32 HL007676NHLBI NIH HHS T32 HL007676-23NIBIB NIH HHS R03 EB011698NIGMS NIH HHS R25 GM056929
Abstract
rationaleHydroxymethyl glutaryl-coenzyme A reductase degradation protein 1 (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 has been studied in the heart, or in cardiac myocytes, where protein quality control is critical for proper heart function.
objectiveThe objective 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
resultsThe effects of small interfering RNA-mediated Hrd1 knockdown were examined in cultured neonatal rat ventricular myocytes. The effects of adeno-associated virus-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 and tunicamycin increased ERAD, as well as adaptive ER stress proteins, and minimally affected cell death. However, when Hrd1 was knocked down, thapsigargin and tunicamycin 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, whereas Hrd1 overexpression preserved cardiac function and decreased apoptosis and attenuated cardiac hypertrophy in the hearts of mice subjected to pressure overload.
conclusionsHrd1 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.
Indexed as
Adaptation, PhysiologicalAnimalsAnimals, NewbornCells, CulturedEndoplasmic ReticulumEndoplasmic Reticulum-Associated DegradationEndoplasmic Reticulum StressGene Knockdown TechniquesMiceMyocytes, CardiacRatsRats, Sprague-DawleyUbiquitin-Protein LigasesSyvn1 protein, mouseUbiquitin-Protein Ligasescardiacendoplasmic reticulum stresshydroxymethylglutaryl CoA reductasesmyocytesprotein foldingproteolysis
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