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IP3R2-mediated Ca2+ release promotes LPS-induced cardiomyocyte pyroptosis via the activation of NLRP3/Caspase-1/GSDMD pathway.
Wu, Qing-Rui; Yang, Hui; Zhang, Hui-Dan; Cai, Yong-Jiang; Zheng, Yan-Xiang; Fang, Heng; Wang, Zi-Fan; Kuang, Su-Juan; Rao, Fang; Huang, Huan-Lei; Deng, Chun-Yu; Chen, Chun-Bo.
Afiliación
  • Wu QR; School of Medicine, South China University of Technology, 510006, Guangzhou, China.
  • Yang H; Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 510080, Guangzhou, Guangdong, China.
  • Zhang HD; Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 510080, Guangzhou, Guangdong, China.
  • Cai YJ; Department of Emergency Medicine, Qilu Hospital of Shandong University, 250012, Jinan, China.
  • Zheng YX; School of Pharmaceutical Sciences, Southern Medical University, 510515, Guangzhou, China.
  • Fang H; Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 510080, Guangzhou, Guangdong, China.
  • Wang ZF; Department of Critical Care Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
  • Kuang SJ; School of Pharmaceutical Sciences, Southern Medical University, 510515, Guangzhou, China.
  • Rao F; Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 510080, Guangzhou, Guangdong, China.
  • Huang HL; School of Medicine, South China University of Technology, 510006, Guangzhou, China.
  • Deng CY; Guangdong Provincial Key Laboratory of Clinical Pharmacology, Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, 510080, Guangzhou, Guangdong, China.
  • Chen CB; Department of Cardiovascular Surgery, Guangdong Provincial People's Hospital, Guangzhou, China.
Cell Death Discov ; 10(1): 91, 2024 Feb 20.
Article en En | MEDLINE | ID: mdl-38378646
ABSTRACT
Pyroptosis plays a crucial role in sepsis, and the abnormal handling of myocyte calcium (Ca2+) has been associated with cardiomyocyte pyroptosis. Specifically, the inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is a Ca2+ release channel in the endoplasmic reticulum (ER). However, the specific role of IP3R2 in sepsis-induced cardiomyopathy (SIC) has not yet been determined. Thus, this study aimed to investigate the underlying mechanism by which IP3R2 channel-mediated Ca2+ signaling contributes to lipopolysaccharide (LPS)-induced cardiac pyroptosis. The SIC model was established in rats by intraperitoneal injection of LPS (10 mg/kg). Cardiac dysfunction was assessed using echocardiography, and the protein expression of relevant signaling pathways was analyzed using ELISA, RT-qPCR, and western blot. Small interfering RNAs (siRNA) and an inhibitor were used to explore the role of IP3R2 in neonatal rat cardiomyocytes (NRCMs) stimulated by LPS in vitro. LPS-induced NLRP3 overexpression and GSDMD-mediated pyroptosis in the rats' heart. Treatment with the NLRP3 inhibitor MCC950 alleviated LPS-induced cardiomyocyte pyroptosis. Furthermore, LPS increased ATP-induced intracellular Ca2+ release and IP3R2 expression in NRCMs. Inhibiting IP3R activity with xestospongin C (XeC) or knocking down IP3R2 reversed LPS-induced intracellular Ca2+ release. Additionally, inhibiting IP3R2 reversed LPS-induced pyroptosis by suppressing the NLRP3/Caspase-1/GSDMD pathway. We also found that ER stress and IP3R2-mediated Ca2+ release mutually regulated each other, contributing to cardiomyocyte pyroptosis. IP3R2 promotes NLRP3-mediated pyroptosis by regulating ER Ca2+ release, and the mutual regulation of IP3R2 and ER stress further promotes LPS-induced pyroptosis in cardiomyocytes.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cell Death Discov Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cell Death Discov Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos