Naoxintong Retards Atherosclerosis by Inhibiting Foam Cell Formation Through Activating Pparα Pathway.

Zeng Wang,Huan Zhao,Zhen Dong,Junbo Ge,Yunzeng Zou,Huairui Shi,Aijun Sun,Xinyu Weng,Buchang Zhao,Kai Hu,Xiao Li,Rongle Liu

doi:10.2174/1566524019666190207143207

Abstract

Backgrounds: We recently reported that Naoxintong (NXT), a China Food and Drug Administration (FDA)-approved cardiac medicine, could reduce the plaque size, but the underlying mechanism remains elusive now.Objective: In this study, we investigated the effects of NXT on foam cell accumulation both in vivo and in vitro and explored related mechanisms.Method: THP-1 cells and bone marrow-derived macrophages were incubated with oxidized low-density lipoprotein (ox-LDL) with/without Naoxintong. ApoE-/- mice fed an atherogenic diet were administered to receive NXT for eight weeks. Macrophage-derived foam cell formation in plaques was measured by immunohistochemical staining. Expression of proteins was evaluated by Western blot. Lentivirus was used to knockdown PPARα in THP-1 cells.Results: After NXT treatment, foam cell accumulation was significantly reduced in atherosclerotic plaques. Further investigation revealed that oxidized low-density lipoprotein (ox-LDL) uptake was significantly decreased and expression of scavenger receptor class A (SR-A) and class B (SR-B and CD36) was significantly downregulated post-NXT treatment. On the other hand, NXT increased cholesterol efflux and upregulated ATP-binding cassette (ABC) transporters (ABCA-1 and ABCG-1) in macrophages. Above beneficial effects of NXT were partly abolished after lentiviral knockdown of PPARα.Conclusion: Our findings suggest that NXT could retard atherosclerosis by inhibiting foam cell formation through reducing ox-LDL uptake and enhancing cholesterol efflux and above beneficial effects are partly mediated through PPARα pathway.

Highlights

Atherosclerosis is a progressive chronic disease of the arteries [1,2,3,4,5]
Further investigation revealed that oxidized low-density lipoprotein uptake was significantly decreased and expression of scavenger receptor class A (SR-A) and class B (SR-B and CD36) was significantly downregulated post-NXT treatment
Our findings suggest that NXT could retard atherosclerosis by inhibiting foam cell formation through reducing oxidized low-density lipoprotein (ox-LDL) uptake and enhancing cholesterol efflux and above beneficial effects are partly mediated through PPARα pathway

Summary

Introduction

The formation of foam cells in vessel walls, which is the result of excessive ox-LDL uptake by monocyte macrophages, is the hallmark event of early atherosclerosis. Lipid metabolism in monocytederived macrophages is a dynamic equilibrium process [6]. Excess ox-LDL uptake and reduced cholesterol efflux in monocyte-derived macrophages are known to accelerate plaque formation in atherosclerosis and are. The uptaken ox-LDL is digested in lysosomes, forming free cholesterol and accumulating in cells. Free cholesterol further stimulates related proteins to upregulate the expression of ABCA-1 and ABCG-1, which are representative members of ATP-binding cassette (ABC) transporters, and promote cholesterol efflux [10, 11]. Rousselle and colleagues reported that CXCL5 could reduce the macrophages foam cell formation in atherosclerosis by increasing the expression of ABCA1 [15]. It is of importance to define the integral factor that is involved in regulating the expression of these lipid metabolic proteins

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Discussion

Conclusion