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Gasdermin D inhibition confers antineutrophil-mediated cardioprotection in acute myocardial infarction
The Journal of Clinical Investigation ( IF 13.3 ) Pub Date : 2021 , DOI: 10.1172/jci151268
Kai Jiang 1 , Zizhuo Tu 1 , Kun Chen 1 , Yue Xu 1 , Feng Chen 1 , Sheng Xu 2 , Tingting Shi 2 , Jie Qian 1 , Lan Shen 3 , John Hwa 4 , Dandan Wang 1 , Yaozu Xiang 1, 2
Affiliation  

Acute myocardial infarction (AMI) induces blood leukocytosis, which correlates inversely with patient survival. The molecular mechanisms leading to leukocytosis in the infarcted heart remain poorly understood. Using an AMI mouse model, we identified gasdermin D (GSDMD) in activated leukocytes early in AMI. We demonstrated that GSDMD is required for enhanced early mobilization of neutrophils to the infarcted heart. Loss of GSDMD resulted in attenuated IL-1β release from neutrophils and subsequent decreased neutrophils and monocytes in the infarcted heart. Knockout of GSDMD in mice significantly reduced infarct size, improved cardiac function, and increased post-AMI survival. Through a series of bone marrow transplantation studies and leukocyte depletion experiments, we further clarified that excessive bone marrow–derived and GSDMD-dependent early neutrophil production and mobilization (24 hours after AMI) contributed to the detrimental immunopathology after AMI. Pharmacological inhibition of GSDMD also conferred cardioprotection after AMI through a reduction in scar size and enhancement of heart function. Our study provides mechanistic insights into molecular regulation of neutrophil generation and mobilization after AMI, and supports GSDMD as a new target for improved ventricular remodeling and reduced heart failure after AMI.

中文翻译:


Gasdermin D 抑制可在急性心肌梗死中赋予抗中性粒细胞介导的心脏保护作用



急性心肌梗死(AMI)会引起血液白细胞增多,这与患者的生存率成反比。导致梗塞心脏白细胞增多的分子机制仍知之甚少。使用 AMI 小鼠模型,我们在 AMI 早期的活化白细胞中鉴定出了 Gasdermin D (GSDMD)。我们证明了 GSDMD 是增强中性粒细胞早期动员至梗塞心脏所必需的。 GSDMD 的缺失导致中性粒细胞 IL-1 β释放减弱,随后梗塞心脏中的中性粒细胞和单核细胞减少。小鼠中 GSDMD 的敲除显着减少了梗塞面积,改善了心脏功能,并增加了 AMI 后的存活率。通过一系列骨髓移植研究和白细胞去除实验,我们进一步阐明,过量的骨髓来源和GSDMD依赖性早期中性粒细胞产生和动员(AMI后24小时)导致了AMI后有害的免疫病理学。 GSDMD 的药理抑制还可以通过减少疤痕大小和增强心脏功能,在 AMI 后提供心脏保护作用。我们的研究为 AMI 后中性粒细胞生成和动员的分子调节提供了机制见解,并支持 GSDMD 作为改善 AMI 后心室重塑和减少心力衰竭的新靶点。
更新日期:2022-01-05
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