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Dysregulated Autophagy and Sarcomere Dysfunction in Patients With Heart Failure With Co-Occurrence of P63A and P380S BAG3 Variants.
Martin, Thomas G; Pak, Hana; Gerhard, Glenn S; Merali, Salim; Merali, Carmen; Lemster, Bonnie; Dubey, Praveen; McTiernan, Charles F; Bristow, Michael R; Feldman, Arthur M; Kirk, Jonathan A.
Afiliação
  • Martin TG; Department of Cell and Molecular Physiology Loyola University Chicago Stritch School of Medicine Maywood IL.
  • Pak H; Department of Cell and Molecular Physiology Loyola University Chicago Stritch School of Medicine Maywood IL.
  • Gerhard GS; Department of Medical Genetics and Molecular Biochemistry Lewis Katz School of Medicine of Temple University Philadelphia PA.
  • Merali S; Temple University School of Pharmacy Philadelphia PA.
  • Merali C; Temple University School of Pharmacy Philadelphia PA.
  • Lemster B; The Heart and Vascular Institute, The University of Pittsburgh School of Medicine Pittsburgh PA.
  • Dubey P; Department of Biomedical Engineering University of Alabama at Birmingham Birmingham AL.
  • McTiernan CF; The Heart and Vascular Institute, The University of Pittsburgh School of Medicine Pittsburgh PA.
  • Bristow MR; Department of Medicine University of Colorado School of Medicine Denver CO.
  • Feldman AM; Department of Medicine, Division of Cardiology The Lewis Katz School of Medicine at Temple University Philadelphia PA.
  • Kirk JA; Department of Cell and Molecular Physiology Loyola University Chicago Stritch School of Medicine Maywood IL.
J Am Heart Assoc ; 12(24): e029938, 2023 12 19.
Article em En | MEDLINE | ID: mdl-38108245
ABSTRACT

BACKGROUND:

Mutations to the co-chaperone protein BAG3 (B-cell lymphoma-2-associated athanogene-3) are a leading cause of dilated cardiomyopathy (DCM). These mutations often impact the C-terminal BAG domain (residues 420-499), which regulates heat shock protein 70-dependent protein turnover via autophagy. While mutations in other regions are less common, previous studies in patients with DCM found that co-occurrence of 2 BAG3 variants (P63A, P380S) led to worse prognosis. However, the underlying mechanism for dysfunction is not fully understood. METHODS AND

RESULTS:

In this study, we used proteomics, Western blots, and myofilament functional assays on left ventricular tissue from patients with nonfailing, DCM, and DCM with BAG363/380 to determine how these mutations impact protein quality control and cardiomyocyte contractile function. We found dysregulated autophagy and increased protein ubiquitination in patients with BAG363/380 compared with nonfailing and DCM, suggesting impaired protein turnover. Expression and myofilament localization of BAG3-binding proteins were also uniquely altered in the BAG3,63/380 including abolished localization of the small heat shock protein CRYAB (alpha-crystallin B chain) to the sarcomere. To determine whether these variants impacted sarcomere function, we used cardiomyocyte force-calcium assays and found reduced maximal calcium-activated force in DCM and BAG363/380. Interestingly, myofilament calcium sensitivity was increased in DCM but not with BAG363/380, which was not explained by differences in troponin I phosphorylation.

CONCLUSIONS:

Together, our data support that the disease-enhancing mechanism for BAG3 variants outside of the BAG domain is through disrupted protein turnover leading to compromised sarcomere function. These findings suggest a shared mechanism of disease among pathogenic BAG3 variants, regardless of location.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Cardiomiopatia Dilatada / Insuficiência Cardíaca Limite: Humans Idioma: En Revista: J Am Heart Assoc Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Cardiomiopatia Dilatada / Insuficiência Cardíaca Limite: Humans Idioma: En Revista: J Am Heart Assoc Ano de publicação: 2023 Tipo de documento: Article