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

doi:10.1016/j.apsb.2023.06.012

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

Acta Pharm Sin B. 2023 Sep;13(9):3756-3769. doi: 10.1016/j.apsb.2023.06.012. Epub 2023 Jun 23.

Authors

Dandong Fang^{1

2

3}, Yu Li^{1

2}, Bo He^{1

2}, Daqian Gu^{1

2}, Mingming Zhang^{1

2}, Jingwen Guo^{1

2}, Hongmei Ren^{1

2}, Xinyue Li^{1

2}, Ziyue Zhang^{1

2}, Ming Tang^{1

2}, Xingbing Li^{1

2}, Donghai Yang^{1

2}, Chunmei Xu^{1

2}, Yijie Hu⁴, Hongyong Wang^{1

2}, Pedro A Jose⁵, Yu Han^{1

2}, Chunyu Zeng^{1

2

6

7}

Affiliations

¹ Department of Cardiology, Daping Hospital, the Third Military Medical University (Army Medical University), Chongqing 400000, China.
² Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing 400010, China.
³ Department of Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210000, China.
⁴ Department of Cardiac Surgery, Daping Hospital, Third Military Medical University, Chongqing 400010, China.
⁵ Division of Renal Disease & Hypertension, the George Washington University School of Medicine & Health Sciences, Washington, DC 20237, USA.
⁶ State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, the Third Military Medical University, Chongqing 400010, China.
⁷ Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences Chongqing 400010, China.

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.

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