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Serum amyloid P component therapeutically attenuates atherosclerosis in mice via its effects on macrophages.

ABSTRACT: Background: A hallmark of atherosclerosis is the formation of macrophage-derived foam cells. Serum amyloid P component (SAP), a member of the pentraxin family of proteins, is known to affect macrophage activation. However, the role of SAP in atherosclerosis is still unclear. Methods: Apolipoprotein E-deficient (Apoe-/-) mice fed a high-fat diet were given intraperitoneal injections of SAP (6 mg/kg) every other day for a total of 2 weeks to characterize atherosclerosis development. Results: We showed that intraperitoneal injection of SAP attenuated atherosclerosis in Apoe-/- mice. Immunostaining of aortic roots indicated that SAP was up-taken by the lesion area. In SAP-treated mice, serum paraoxonase1 (PON1) activity was increased whereas high-density lipoprotein inflammatory index (HII) was reduced. The cholesterol efflux rate in macrophages was elevated along with the expression of cholesterol efflux proteins. Through bioinformatics analysis followed by experimental validation, we found that proline/serine-rich coiled-coil protein 1 (Psrc1) was an important downstream effector of SAP in macrophages. Conclusions: Our findings reveal an anti-atherosclerotic role of SAP and extend the current knowledge regarding this molecule as a marker for atherosclerosis.

SUBMITTER: Xi D

PROVIDER: S-EPMC6010983 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Serum amyloid P component therapeutically attenuates atherosclerosis in mice via its effects on macrophages.

Xi Dan D Zhao Jinzhen J Guo Kai K Hu Lu L Chen Hui H Fu Weijun W Lai Wenyan W Guo Zhigang Z

Theranostics 20180511 12

Background: A hallmark of atherosclerosis is the formation of macrophage-derived foam cells. Serum amyloid P component (SAP), a member of the pentraxin family of proteins, is known to affect macrophage activation. However, the role of SAP in atherosclerosis is still unclear. Methods: Apolipoprotein E-deficient (Apoe-/-) mice fed a high-fat diet were given intraperitoneal injections of SAP (6 mg/kg) every other day for a total of 2 weeks to characterize atherosclerosis de ...[more]

PMID: 29930724

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Project description:Background and Purpose: Atherosclerosis is an underlying cause of coronary heart disease. Foam cell, a hallmark of atherosclerosis, is prominently derived from monocyte-differentiated macrophage, and vascular smooth muscle cells (VSMCs) through unlimitedly phagocytizing oxidized low-density lipoprotein (oxLDL). Therefore, the inhibition of monocyte adhesion to endothelium and uptake of oxLDL might be a breakthrough point for retarding atherosclerosis. Formononetin, an isoflavone extracted from Astragalus membranaceus, has exhibited multiple inhibitory effects on proatherogenic factors, such as obesity, dyslipidemia, and inflammation in different animal models. However, its effect on atherosclerosis remains unknown. In this study, we determined if formononetin can inhibit atherosclerosis and elucidated the underlying molecular mechanisms. Methods: ApoE deficient mice were treated with formononetin contained in high-fat diet for 16 weeks. After treatment, mouse aorta, macrophage and serum samples were collected to determine lesions, immune cell profile, lipid profile and expression of related molecules. Concurrently, we investigated the effect of formononetin on monocyte adhesion, foam cell formation, endothelial activation, and macrophage polarization in vitro and in vivo. Results: Formononetin reduced en face and aortic root sinus lesions size. Formononetin enhanced lesion stability by changing the composition of plaque. VSMC- and macrophage-derived foam cell formation and its accumulation in arterial wall were attenuated by formononetin, which might be attributed to decreased SRA expression and reduced monocyte adhesion. Formononetin inhibited atherogenic monocyte adhesion and inflammation. KLF4 negatively regulated the expression of SRA at transcriptional and translational level. Conclusions: Our study demonstrate that formononetin can substantially attenuate the development of atherosclerosis via regulation of interplay between KLF4 and SRA, which suggests the formononetin might be a novel therapeutic approach for inhibition of atherosclerosis.

Dataset Information

Serum amyloid P component therapeutically attenuates atherosclerosis in mice via its effects on macrophages.

Publications

Serum amyloid P component therapeutically attenuates atherosclerosis in mice via its effects on macrophages.

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