Endoplasmic reticulum stress impairs cardiomyocyte contractility through JNK-dependent upregulation of BNIP3

Autor(es)

Takano, Ana P. C. ^[1] ; Campos, Juliane C. ^[1] ; Voltarelli, Vanessa A. ^[6] ; Ferreira, Julio C. B. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Sch Phys Educ & Sport, Av Prof Mello Moraes 65, BR-05508900 Butanta, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF CARDIOLOGY; v. 272, p. 194-201, DEC 1 2018.
• Citações Web of Science: 2

Resumo

Background: Disruption of endoplasmic reticulum (ER) homeostasis is a common feature of cardiac diseases. However, the signaling events involved in ER stress-induced cardiac dysfunction are still elusive. Here, we uncovered a mechanism by which disruption of ER homeostasis impairs cardiac contractility. Methods/results: We found that ER stress is associated with activation of JNK and upregulation of BNIP3 in a postmyocardial infarction (MI) model of cardiac dysfunction. Of interest, 4-week treatment of MI rats with the chemical ER chaperone 4-phenylbutyrate (4PBA) prevented both activation of JNK and upregulation of BNIP3, and improved cardiac contractility. We showed that disruption of ER homeostasis by treating adult rat cardiomyocytes in culture with tunicamycin leads to contractile dysfunction through JNK signaling pathway. Upon ER stress JNK upregulates BNIP3 in a FOXO3a-dependent manner. Further supporting a BNIP3 mechanism for ER stress-induced deterioration of cardiac function, siRNA-mediated BNIP3 knockdown mitigated ER stressinduced cardiomyocyte dysfunction by reestablishing sarcoplasmic reticulum Ca(2+)content. Conclusions: Collectively, our data identify JINK-dependent upregulation of BNIP3 as a critical process involved in ER stress-induced cardiomyocyte contractile dysfunction and highlight 4PBA as a potential intervention to counteract ER stress-mediated BNIP3 upregulation in failing hearts. (C) 2018 Elsevier B.V. All rights reserved. (AU)

• Processo FAPESP: 15/22814-5 - Câncer e coração: novos paradigmas de diagnóstico e tratamento
• Beneficiário: Carlos Eduardo Negrão
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 16/09611-0 - Cardiotoxicidade induzida pela doxorrubicina: caracterização da sinalização mitocondrial retrógrada ativada pelo desequilíbrio proteostático
• Beneficiário: Luiz Henrique Marchesi Bozi
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado