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

Dandong Fang; Yu LI; Bo HE; Daqian GU; Mingming Zhang; Jingwen Guo; Hongmei Ren; Xinyue LI; Ziyue Zhang; Ming Tang; Xingbing LI; Donghai Yang; Chunmei XU; Yijie HU; Hongyong Wang; Pedro A Jose; Yu Han; Chunyu Zeng

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

Author: Dandong FANG ¹ ; Yu LI ¹ ; Bo HE ¹ ; Daqian GU ¹ ; Mingming ZHANG ¹ ; Jingwen GUO ¹ ; Hongmei REN ¹ ; Xinyue LI ¹ ; Ziyue ZHANG ¹ ; Ming TANG ¹ ; Xingbing LI ¹ ; Donghai YANG ¹ ; Chunmei XU ¹ ; Yijie HU ² ; Hongyong WANG ¹ ; Pedro A JOSE ³ ; Yu HAN ¹ ; Chunyu ZENG ¹
Author Information

1. Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.
2. Department of Cardiac Surgery, Daping Hospital, Third Military Medical University, Chongqing 400010, China.
3. Division of Renal Disease & Hypertension, the George Washington University School of Medicine & Health Sciences, Washington, DC 20237, USA.
Publication Type:Journal Article
Keywords: Cholecystokinin B receptor; Gastrin; Inflammation; Lipopolysaccharide; Macrophage; Peroxisome proliferators-activated receptor α; Sepsis-induced myocardial dysfunction; Toll-like receptor 4
From: Acta Pharmaceutica Sinica B 2023;13(9):3756-3769
CountryChina
Language:English
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 (Cckbr), 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 Cckbr-deficient mice. The intravenous injection of bone marrow macrophages (BMMs) overexpressing Cckbr reduced LPS-induced myocardial dysfunction. Furthermore, gastrin treatment inhibited toll-like receptor 4 (TLR4) expression through the peroxisome proliferator-activated receptor α (PPAR-α) 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.