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15-Lipoxygenase-2 Deficiency Induces a Dysfunction in Macrophages that can be Restored by Salidroside

ABSTRACT: 15-Lipoxygenase-2 (15-LOX-2) is thought to regulate inflammation and immunological function; however, its mechanisms of action are still unclear. Furthermore, it has been reported that salidroside has anti-inflammatory properties, but its role in macrophage function is not yet understood. In this study, we aimed to determine how 15-LOX-2 expression levels affect the function of macrophages and the effect of salidroside on 15-LOX-2-deficient macrophages. We used multiple functional genetic strategies to determine 15-LOX-2 function in macrophages. 15-LOX-2 deficiency promoted phagocytosis and the proliferation of macrophages and impaired their apoptosis. Mechanistically, the expression levels of cyclophilin B (CypB) were upregulated in 15-LOX-2-deficient Ana-1 macrophages, whereas those of caspase-3 were downregulated. Furthermore, RNA-seq analysis showed that inflammation, complement, and TNF-α signaling pathways were all activated in 15-LOX-2-deficient Ana-1 macrophages. Treatment of 15-LOX-2-deficient macrophages with salidroside, a natural product derived from Rhodiola species, effectively reversed the effects of 15-LOX-2 deficiency on caspase-3 and CypB levels, as well as on apoptosis and proliferation. In conclusion, our study shows a newly identified link between 15-LOX-2 deficiency and salidroside in regulating macrophage survival, proliferation, and function. Salidroside may be a promising therapeutic strategy for treating inflammation-related diseases resulting from 15-LOX-2 deficiency.

ORGANISM(S): Mus musculus

PROVIDER: GSE184840 | GEO | 2021/10/04

REPOSITORIES: GEO

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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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15-Lipoxygenase-2 Deficiency Induces a Dysfunction in Macrophages that can be Restored by Salidroside

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