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Inhibition of Soluble Epoxide Hydrolase in Macrophages Ameliorates the Formation of Foam Cells - Role of Heme Oxygenase-1

Inhibition of Soluble Epoxide Hydrolase in Macrophages Ameliorates the Formation of Foam Cells - Role of Heme Oxygenase-1

Hongchun Peng, Jianjun Tang, Shuiping Zhao, Li Shen, Danyan Xu

Circ J. 2019 Nov 25;83(12):2555-2566.

PMID: 31666457

Abstract:

Background:
Accumulation of foam cells in the neointima represents an early stage of atherosclerosis. 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl) urea (TPPU), a novel soluble epoxide hydrolase inhibitor (sEHi), effectively elevates epoxyeicosatrienoic acid (EET) levels. The effects of EETs on macrophages foam cells formation are poorly understood.Methods and Results:Incubation of foam cells with TPPU markedly ameliorate cholesterol deposition in oxidized low-density lipoprotein (oxLDL)-loaded macrophages by increasing the levels of EETs. Notably, TPPU treatment significantly inhibits oxLDL internalization and promotes cholesterol efflux. The elevation of EETs results in a decrease of class A scavenger receptor (SR-A) expression via downregulation of activator protein 1 (AP-1) expression. Additionally, TPPU selectively increases protein but not the mRNA level of ATP-binding cassette transporter A1 (ABCA1) through the reduction of calpain activity that stabilizes the protein. Moreover, TPPU treatment reduces the cholesterol content of macrophages and inhibits atherosclerotic plaque formation in apolipoprotein E-deficient mice. These changes induced by TPPU are dependent on heme oxygenase-1 (HO-1) activation.
Conclusions:
The present study findings elucidate a precise mechanism of regulating cholesterol uptake and efflux in macrophages, which involves the prevention of atherogenesis by increasing the levels of EETs with TPPU.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1222780337	TPPU		1222780-33-7	Price

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