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Leukotriene B4 receptor 1 antagonist in combination with kinase MST1/2 inhibitor has potential for treatment of myocardial infarction

ABSTRACT: Timely inhibition of inflammation and initiation of resolution are important for the repair of injured tissues. Pharmacological inhibition of mammalian STE20-like protein kinase 1/2 (MST1/2) with XMU-MP-1 might augment tissue regeneration and repair by suppressing apoptosis and increasing cell proliferation. However, MST1 has anti-inflammatory activity, inhibition of which may result in therapy failure. Here, we identified an approach with the potential to overcome this limitation by protecting against cardiac inflammation resulting from inhibition of MST1 in macrophages. We found exacerbation of cardiac dysfunction in LysMCre-mediated Mst1/2-deficient mice after myocardial infarction (MI). This effect was attributed to a shift of macrophage subtypes from those expressing Cxcl2 and Cd163 toward those with Ccl2 and Ccl4 expression. Mass spectrometry identified leukotriene B4 (LTB4) as the lipid mediator that was upregulated in the absence of MST1. We found that MST1 phosphorylated 5-lipoxygenase (5-LOX) at its T218 residue, disrupting the interaction between 5-LOX and 5-LOX-activating protein, and resulting in reduction of LTB4 production. By contrast, a 5-LOXT218A variant showed no response to MST1. Moreover, treatment of peritoneal macrophages with LTB4 or with medium conditioned by Mst1-deficient macrophages resulted in high Ccl2 and Ccl4 expression and low Cxcl2 and Cd163 expression, except when the cells were co-treated with the LTB4 receptor 1 (BLT1) antagonist CP105696. Furthermore, CP105696 ameliorated cardiac dysfunction in LysMCre-mediated Mst1/2-deficient mice and enhanced cardiac repair in wild-type mice treated with XMU-MP-1 after MI. The combination of an MST1/2 inhibitor and a BLT1 antagonist represents a promising strategy for combatting the effects of MI.

ORGANISM(S): Mus musculus

PROVIDER: GSE181935 | GEO | 2021/12/13

REPOSITORIES: GEO

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Project description:Background: Galectin-3 is upregulated in heart disease, and its inhibition has been reported to confer benefits on cardiac remodeling and dysfunction. It remains unknown whether galectin-3 plays a biological role in a setting of dilated cardiomyopathy (DCM). We determined galectin-3 expression in transgenic (TG) mice with cardiac-restricted overexpression of mammalian sterile 20-like kinase 1 (Mst1-TG), and studied the effects of pharmacological and genetic inhibition of galectin-3 on the DCM phenotype. Methods and results: The DCM phenotype of male Mst1-TG mice was assessed at 2, 3 and 6 months of age. Galectin-3 deletion in Mst1-TG mice was achieved by cross-breeding Mst1-TG with galectin-3 knockout (KO) mice to produce genotypes of non-TG (nTG), KO, Mst1-TG, and Mst1-TG mice with partial or complete deletion of the galectin-3 gene. Pharmacological inhibition of galectin-3 was tested by treating Mst1-TG mice with modified citrus pectin for 4 months. Changes in the DCM phenotype were assessed by serial echocardiography, ECG recording and biochemical assays. Mst1-TG mice exhibited upregulated levels of cardiac galectin-3 expression by 40~50-fold, atrial dilatation, reduced left ventricular (LV) ejection fraction, increased LV volume at systole and diastole, atrial conduction delay, severe cardiac fibrosis, and upregulated fibrosis-related genes. Galectin-3 gene deletion in Mst1-TG mice attenuates increased LV volume at systole and diastole, atrial conduction delay and cardiac fibrogenesis. Treatment with modified citrus pectin in Mst1-TG mice did not confer benefit on the DCM phenotype, possibly due to the very high expression of galectin-3. Conclusion: Galectin-3 expression is markedly increased in Mst1-TG hearts exhibiting DCM. Galectin-3 gene deletion effectively suppressed cardiac fibrotic signaling and LV dilatation, and was associated with better function. Thus, suppression of galectin-3 expression may represent a potential therapeutic approach in DCM. The development of new galectin-3 inhibitors are warranted.

Project description:To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, 12/15 lipoxygenase (12/15-LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that 12/15-LOX transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in 12/15-LOX transgenic mice with advancing age, and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (Mcp-1) was up-regulated in 12/15-LOX transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells, but not in cardiomyocytes. Inhibition of Mcp-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in 12/15-LOX transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac Mcp-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition. Heart failure is still one of the leading causes of death worldwide. Therefore, it is important to elucidate the underlying mechanisms of heart failure and develop more effective treatments for this condition. To clarify the molecular mechanisms of heart failure, we performed microarray analysis using cardiac tissue samples obtained from a hypertensive heart failure model (Dahl salt-sensitive rats). ~300 genes showed significant changes of expression in the failing hearts compared with control hearts. Among the genes analyzed, 12/15-lipoxygenase (12/15-LOX) was most markedly up-regulated in failing hearts compared with control hearts .

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Leukotriene B4 receptor 1 antagonist in combination with kinase MST1/2 inhibitor has potential for treatment of myocardial infarction

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