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Upregulation of PTPN1 aggravates endotoxemia-induced cardiac dysfunction through inhibiting mitophagy.
Song, Qixiang; Ma, Heng; Zhu, Lili; Qi, Zehong; Lan, Zijun; Liu, Ke; Zhang, Huali; Wang, KangKai; Wang, Nian.
Afiliación
  • Song Q; Department of Pathophysiology, School of Basic Medical Science, Central South University, 110 Xiangya Road, Changsha 410083, China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, 110 Xiangya Road, Changsha 410083, China.
  • Ma H; Department of Pathophysiology, School of Basic Medical Science, Central South University, 110 Xiangya Road, Changsha 410083, China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, 110 Xiangya Road, Changsha 410083, China.
  • Zhu L; Department of Pathophysiology, School of Basic Medical Science, Central South University, 110 Xiangya Road, Changsha 410083, China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, 110 Xiangya Road, Changsha 410083, China.
  • Qi Z; Department of Pathophysiology, School of Basic Medical Science, Central South University, 110 Xiangya Road, Changsha 410083, China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, 110 Xiangya Road, Changsha 410083, China.
  • Lan Z; Department of Pathophysiology, School of Basic Medical Science, Central South University, 110 Xiangya Road, Changsha 410083, China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, 110 Xiangya Road, Changsha 410083, China.
  • Liu K; Department of Pathophysiology, School of Basic Medical Science, Central South University, 110 Xiangya Road, Changsha 410083, China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, 110 Xiangya Road, Changsha 410083, China.
  • Zhang H; Department of Pathophysiology, School of Basic Medical Science, Central South University, 110 Xiangya Road, Changsha 410083, China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, 110 Xiangya Road, Changsha 410083, China.
  • Wang K; Department of Pathophysiology, School of Basic Medical Science, Central South University, 110 Xiangya Road, Changsha 410083, China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, 110 Xiangya Road, Changsha 410083, China. Electronic address: wangkangkai@csu.edu.cn
  • Wang N; Department of Pathophysiology, School of Basic Medical Science, Central South University, 110 Xiangya Road, Changsha 410083, China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, 110 Xiangya Road, Changsha 410083, China. Electronic address: wangnian@csu.edu.cn.
Int Immunopharmacol ; 126: 111315, 2024 Jan 05.
Article en En | MEDLINE | ID: mdl-38043267
OBJECTIVES: To investigate the role of protein tyrosine phosphatase non-receptor type 1 (PTPN1) in mitophagy during sepsis and its underlying mechanisms and determine the therapeutic potential of PTPN1 inhibitors in endotoxemia-induced cardiac dysfunction. METHODS: A mouse model of endotoxemia was established by administering an intraperitoneal injection of lipopolysaccharide (LPS). The therapeutic effect of targeting PTPN1 was evaluated using its inhibitor Claramine (CLA). Mitochondrial structure and function as well as the expression of mitophagy-related proteins were evaluated. Rat H9c2 cardiomyocytes were exposed to mouse RAW264.7 macrophage-derived conditioned medium. Cryptotanshinone, a specific p-STAT3 (Y705) inhibitor, was used to confirm the role of STAT3 in PTPN1-mediated mitophagy following LPS exposure. Electrophoretic mobility shift and dual luciferase reporter assays were performed to discern the mechanisms by which STAT3 regulated the expression of PINK1 and PRKN. RESULTS: CLA alleviated LPS-induced myocardial damage, cardiac dysfunction, and mitochondrial injury and dysfunction in the mouse heart. PTPN1 upregulation exacerbated LPS-induced mitochondrial injury and dysfunction in H9c2 cardiomyocytes, but inhibited LPS-induced mitophagy. LPS promoted the interaction between PTPN1 and STAT3 and reduced STAT3 phosphorylation at Tyr705 (Y705), which was required to inhibit mitophagy by PTPN1. Upon LPS stimulation, PTPN1 negatively regulated the transcription of PINK1 and PRKN through dephosphorylation of STAT3 at Y705. STAT3 regulated the transcription of PINK1 and PRKN by binding to STAT3-responsive elements in their promoters. CONCLUSION: PTPN1 upregulation aggravates endotoxemia-induced cardiac dysfunction by impeding mitophagy through dephosphorylation of STAT3 at Y705 and negative regulation of PINK1 and PRKN transcription.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Endotoxemia / Cardiopatías Límite: Animals Idioma: En Revista: Int Immunopharmacol Asunto de la revista: ALERGIA E IMUNOLOGIA / FARMACOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Endotoxemia / Cardiopatías Límite: Animals Idioma: En Revista: Int Immunopharmacol Asunto de la revista: ALERGIA E IMUNOLOGIA / FARMACOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Países Bajos