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Targeting STIM1 attenuates LPS-induced cardiac dysfunction by reshaping calcium homeostasis and mitochondrial
Qing-Rui Wu1, Li-Bo Luo2, Hui Yang3
1Guangdong 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; State Key Laboratory of Respiratory Disease, Institute of Pulmonary Diseases, Department of Critical Care Medicine, Guangzhou Chest Hospital, Guangzhou Medical University, Guangzhou, 510095, China.
Insights
STIM1 protein upregulation worsens sepsis-induced cardiomyopathy (SICM) by disrupting calcium handling and mitochondrial function. Targeting STIM1 offers a potential therapeutic strategy for SICM.
Area of Science:
- Cardiology
- Molecular Biology
- Cellular Biology
Background:
- Sepsis-induced cardiomyopathy (SICM) involves disrupted calcium homeostasis and mitochondrial dysfunction.
- Stromal interaction molecule 1 (STIM1) plays a key role in calcium regulation.
- The specific role of STIM1 in SICM pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the role and mechanism of STIM1 in sepsis-induced cardiomyopathy (SICM).
- To determine if modulating STIM1-mediated calcium handling can alleviate SICM.
Main Methods:
- Established a rat model of sepsis using lipopolysaccharide (LPS).
- Utilized myocardial-specific STIM1 knockdown in septic rats.
- Employed the calcium influx inhibitor BTP2.
- Investigated STIM1's mechanism in LPS-treated cardiomyocytes.
Main Results:
- STIM1 protein was upregulated in sepsis-induced cardiomyopathy (SICM).
- STIM1 knockdown improved cardiac function in septic rats.
- BTP2 alleviated LPS-induced cardiomyopathy by enhancing calcium and mitochondrial function.
- STIM1 amplifies calcium entry, leading to overload, mitochondrial fragmentation, ROS production, and NLRP3 inflammasome-mediated pyroptosis.
Conclusions:
- STIM1 promotes SICM by exacerbating calcium overload, mitochondrial dysfunction, and cardiomyocyte pyroptosis.
- Targeting STIM1 presents a promising therapeutic avenue for treating sepsis-induced cardiomyopathy (SICM).
Abstract:
Dysregulated calcium homeostasis and mitochondrial impairment are critical factors in the pathogenesis of sepsis-induced cardiomyopathy (SICM). STIM1 is crucial for maintaining calcium homeostasis. However, whether improving STIM1-mediated calcium handling can alleviate SICM remains unknown. This study aims to clarify the mechanism and the role of STIM1 in SICM. In this study, we first established a rat model of sepsis induced by LPS and clarified that the upregulation of STIM1 protein is associated with SICM. Myocardial-specific knockdown of STIM1 significantly improved cardiac function in septic rats. Moreover, using the calcium influx inhibitor BTP2, we elucidated that BTP2 could alleviate SICM by improving calcium handling and mitochondrial function. Subsequently, we treated cardiomyocytes with LPS to explore the mechanism by which STIM1 promotes SICM. The results demonstrated that STIM1 amplifies store-operated calcium entry, triggering concomitant cytosolic and mitochondrial calcium overload. This induces Drp1-dependent mitochondrial fragmentation and dysfunction, resulting in elevated ROS production and subsequent activation of the NLRP3 inflammasome-mediated pyroptosis in cardiomyocytes, ultimately leading to SICM. In conclusion, this study indicate that STIM1 promotes calcium overload, thereby facilitating mitochondrial dysfunction and ultimately resulting in pyroptosis. Targeting STIM1 may thus represent a promising therapeutic strategy for SICM.
