IP3R2-mediated Ca²⁺ release promotes LPS-induced cardiomyocyte pyroptosis via the activation of NLRP3/Caspase-1/GSDMD pathway

Wu, Qing-Rui1,2; Yang, Hui2; Zhang, Hui-Dan3; Cai, Yong-Jiang4; Zheng, Yan-Xiang2; Fang, Heng5; Wang, Zi-Fan4; Kuang, Su-Juan2; Rao, Fang1,2; Huang, Huan-Lei6; Deng, Chun-Yu1,2,4; Chen, Chun-Bo1,7

2024-02-20

10.1038/s41420-024-01840-8

CELL DEATH DISCOVERY   影响因子和分区

2058-7716

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.

SCI

英语

通讯

Cell Biology

Cell Biology

WOS:001167901800002

SPRINGERNATURE

Web of Science

1.South China Univ Technol, Sch Med, Guangzhou 510006, Peoples R China
2.Southern Med Univ, Guangdong Prov Peoples Hosp, Guangdong Acad Med Sci, Res Ctr Med Sci,Guangdong Prov Key Lab Clin Pharma, Guangzhou 510080, Guangdong, Peoples R China
3.Shandong Univ, Dept Emergency Med, Qilu Hosp, Jinan 250012, Peoples R China
4.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou 510515, Peoples R China
5.Southern Med Univ, Guangdong Prov Peoples Hosp, Guangdong Acad Med Sci, Dept Crit Care Med, Guangzhou, Peoples R China
6.Guangdong Prov Peoples Hosp, Dept Cardiovasc Surg, Guangzhou, Peoples R China
7.Southern Univ Sci & Technol, Clin Med Coll 2, Shenzhen Peoples Hosp, Affiliated Hosp 1,Dept Crit Care Med,Jinan Univ, Shenzhen 518020, Peoples R China

Wu, Qing-Rui,Yang, Hui,Zhang, Hui-Dan,et al. IP3R2-mediated Ca²⁺ release promotes LPS-induced cardiomyocyte pyroptosis via the activation of NLRP3/Caspase-1/GSDMD pathway[J]. CELL DEATH DISCOVERY,2024,10(1).

Wu, Qing-Rui.,Yang, Hui.,Zhang, Hui-Dan.,Cai, Yong-Jiang.,Zheng, Yan-Xiang.,...&Chen, Chun-Bo.(2024).IP3R2-mediated Ca²⁺ release promotes LPS-induced cardiomyocyte pyroptosis via the activation of NLRP3/Caspase-1/GSDMD pathway.CELL DEATH DISCOVERY,10(1).

Wu, Qing-Rui,et al."IP3R2-mediated Ca²⁺ release promotes LPS-induced cardiomyocyte pyroptosis via the activation of NLRP3/Caspase-1/GSDMD pathway".CELL DEATH DISCOVERY 10.1(2024).