Gastrin attenuates sepsis-induced myocardial dysfunction by down-regulation of TLR4 expression in macrophages

Dandong Fang, Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.
Yu Li, Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.
Bo He, Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.
Daqian Gu, Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.
Mingming Zhang, Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.
Jingwen Guo, Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.
Hongmei Ren, Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.
Xinyue Li, Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.
Ziyue Zhang, Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.
Ming Tang, Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.
Xingbing Li, Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.
Donghai Yang, Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.
Chunmei Xu, Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.
Yijie Hu, Department of Cardiac Surgery, Daping Hospital, Third Military Medical University, Chongqing 400010, China.
Hongyong Wang, Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.
Pedro A. Jose, Division of Renal Disease & Hypertension, the George Washington University School of Medicine & Health Sciences, Washington, DC 20237, USA.
Yu Han, Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.
Chunyu Zeng, Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.

Document Type

Journal Article

Publication Date

9-1-2023

Journal

Acta pharmaceutica Sinica. B

Volume

13

Issue

9

DOI

10.1016/j.apsb.2023.06.012

Keywords

Cholecystokinin B receptor; Gastrin; Inflammation; Lipopolysaccharide; Macrophage; Peroxisome proliferators-activated receptor α; Sepsis-induced myocardial dysfunction; Toll-like receptor 4

Abstract

Myocardial dysfunction is the most serious complication of sepsis. Sepsis-induced myocardial dysfunction (SMD) is often associated with gastrointestinal dysfunction, but its pathophysiological significance remains unclear. The present study found that patients with SMD had higher plasma gastrin concentrations than those without SMD. In mice, knockdown of the gastrin receptor, cholecystokinin B receptor (), aggravated lipopolysaccharide (LPS)-induced cardiac dysfunction and increased inflammation in the heart, whereas the intravenous administration of gastrin ameliorated SMD and cardiac injury. Macrophage infiltration plays a significant role in SMD because depletion of macrophages by the intravenous injection of clodronate liposomes, 48 h prior to LPS administration, alleviated LPS-induced cardiac injury in -deficient mice. The intravenous injection of bone marrow macrophages (BMMs) overexpressing reduced LPS-induced myocardial dysfunction. Furthermore, gastrin treatment inhibited toll-like receptor 4 () expression through the peroxisome proliferator-activated receptor (PPAR-) signaling pathway in BMMs. Thus, our findings provide insights into the mechanism of the protective role of gastrin/CCKBR in SMD, which could be used to develop new treatment modalities for SMD.

Department

Medicine

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