Gasdermin D inhibition confers antineutrophil-mediated cardioprotection in acute myocardial infarction
Year: 2021
Type: article
Abstract: 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.
DOI: 10.1172/jci151268
Authors: Kai Jiang, Zizhuo Tu, Kun Chen, Yue Xu, Feng Chen, Sheng Xu, Tingting Shi, Jie Qian, Lan Shen, John Hwa, Dandan Wang, Yaozu Xiang
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,200
Funders: National Natural Science Foundation of China, Tongji University, National Institutes of Health, National Outstanding Youth Science Fund Project of National Natural Science Foundation of China, National Key Research and Development Program of China, Fundamental Research Funds for the Central Universities, National Center for Advancing Translational Sciences
OpenAlex ID: W3211877172