IP3R2-mediated Ca 2+ release promotes LPS-induced cardiomyocyte pyroptosis via the activation of NLRP3/Caspase-1/GSDMD pathway.
Qing-Rui WuHui YangHui-Dan ZhangYong-Jiang CaiYan-Xiang ZhengHeng FangZi-Fan WangSu-Juan KuangFang RaoHuan-Lei HuangChun-Yu DengChun-Bo ChenPublished in: Cell death discovery (2024)
Pyroptosis plays a crucial role in sepsis, and the abnormal handling of myocyte calcium (Ca 2+ ) has been associated with cardiomyocyte pyroptosis. Specifically, the inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is a Ca 2+ 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 Ca 2+ 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 Ca 2+ release and IP3R2 expression in NRCMs. Inhibiting IP3R activity with xestospongin C (XeC) or knocking down IP3R2 reversed LPS-induced intracellular Ca 2+ 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 Ca 2+ release mutually regulated each other, contributing to cardiomyocyte pyroptosis. IP3R2 promotes NLRP3-mediated pyroptosis by regulating ER Ca 2+ release, and the mutual regulation of IP3R2 and ER stress further promotes LPS-induced pyroptosis in cardiomyocytes.
Keyphrases
- lps induced
- inflammatory response
- nlrp inflammasome
- high glucose
- endoplasmic reticulum
- toll like receptor
- signaling pathway
- heart failure
- left ventricular
- angiotensin ii
- intensive care unit
- oxidative stress
- acute kidney injury
- poor prognosis
- endothelial cells
- immune response
- induced apoptosis
- drug delivery
- atrial fibrillation
- cancer therapy
- long non coding rna
- reactive oxygen species
- endoplasmic reticulum stress
- cell proliferation
- smoking cessation