抄録
Background: MI (myocardial infarction) is an ischemic heart disease caused by coronary occlusion. In MI, cardiomyocytes undergo necrosis and intracellular proteins from dead cells are released, resulting in the infiltration of various inflammatory cells to the infarct area. These inflammatory cells promote further inflammation by producing pro-inflammatory cytokines, which leads to the deterioration of cardiac functions.
Leukotriene B4 receptor type 1 (BLT1) is a high affinity G-protein coupled receptor for leukotriene B4 (LTB4) and is abundantly expressed on inflammatory cells. BLT1 is known to be involved in various diseases of inflammation. However, the function of BLT1 in MI is unclear. Therefore, in the current study, we set out to elucidate the role of BLT1 in MI using BLT1 KO mice.
Methods: Male mice (8-10 weeks old) were subjected to permanent left anterior descending coronary artery ligation under anesthetized conditions. The infiltration of leukocytes to the infarct area was evaluated by immunohistochemistry, and the expression levels of inflammatory genes in the infarcted hearts were determined using real time RT-PCR. A BLT1 antagonist, ONO-4057, was administered through the tail vain immediately after the MI operation.
Result: We found that the LTB4 production and mRNA expression level of BLT1 were increased in infarcted mouse hearts. Leukocytes expressing BLT1 were found at the infarcted area in the mouse and human infarcted hearts. In BLT1 KO mice, infiltration of leukocytes, mRNA expression level of pro-inflammatory genes, and cell death in infarcted hearts were decreased compared with WT mice after MI. These led to reduced mortality and improved cardiac function of BLT1 KO mice after MI. Bone-marrow transplantation studies revealed that BLT1 expressed on bone-marrow-derived cells was responsible for the exacerbation of inflammation in the infarcted hearts. Furthermore, ONO-4057 administration attenuated the inflammatory responses in MI-operated hearts, which resulted in reduced mortality and improved cardiac function after MI.
Conclusions: The current study demonstrates that BLT1 plays unfavorable roles in MI and could represent a new therapeutic target for MI.
