Methionine sulfoxide reductase A attenuates atherosclerosis via repairing dysfunctional HDL in scavenger receptor class B type I deficient mice

Abstract

High‐density lipoprotein (HDL), a well‐known atheroprotective factor, can be converted to proatherogenic particles in chronic inflammation. HDL‐targeted therapeutic strategy for atherosclerotic cardiovascular disease (CVD) is currently under development. This study aims to assess the role of methionine sulfoxide reductase A (MsrA) in abnormal HDL and its related disorders in scavenger receptor class B type I deficient (SR‐BI−/−) mice. First, we demonstrated that MsrA overexpression attenuated ROS level and inflammation in HepG2 cells. For the in vivo study, SR‐BI−/− mice were intravenously injected with lentivirus to achieve hepatic MsrA overexpression. High‐level hepatic MsrA significantly reduced the plasma free cholesterol contents, improved HDL functional proteins apolipoprotein A‐I (apoAI), apoE, paraoxonase1 (PON1), and lecithin:cholesterol acyltransferase (LCAT), while decreased the pro‐inflammatory property of dysfunctional HDL, contributing to reduced atherosclerosis and hepatic steatosis in Western diet‐fed mice. Furthermore, the study revealed that hepatic MsrA altered the expression of several genes controlling HDL biogenesis, cholesterol esterification, cholesterol uptake mediated by low‐density lipoprotein receptor (LDLR) and biliary excretion, as well as suppressed nuclear factor κB (NF‐κB) signaling pathway, which largely relied on liver X receptor alpha (LXRα)‐upregulation. These results provide original evidence that MsrA may be a promising target for the therapy of dysfunctional HDL‐related CVD.

Hepatic paraoxonase 1 ameliorates dysfunctional high-density lipoprotein and atherosclerosis in scavenger receptor class B type I deficient mice

“…Briefly, p-nitrophenol butyrate was used as a substrate to release p-nitrophenoxide under the action of phospholipase and transacylase of LCAT, and the increase of absorbance at 400 nm (A 400 ) was determined to quantify the activity of LCAT. One unit of LCAT activity was defined as 1 μmol of p-nitrophenoxide formed per hour, measuring the increase of A 400 expressed as U/mL plasma (29). Plasma MPO activity was measured using the enzymatic colorimetric assay kit according to the instruction (Nanjing Jiancheng Bioengineering Institute).…”

“…The cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% (v/v) FBS (Gibco, Thermo Fisher Scientific, MA, USA) and 1% penicillin/streptomycin (Biosharp, Hefei, China) at 37 ℃ in 5% CO 2 atmosphere. In order to detect the effect of PON1 on plasma HDL function in Scarb1 -/mice, HDLcontaining plasma was prepared by PEG-6000 (CAS 25322-68-3, Sigma-Aldrich) precipitation method to remove apolipoprotein B (APOB)-containing LDL and very lowdensity lipoprotein (VLDL) (29). To detect the impact of HDL on cholesterol flux of macrophages, the RAW264.7 cells were loaded with 50 μg/mL ox-LDL for 12 h, then incubated in fresh DMEM with 7% APOB-depleted plasma for 24 h. Lipid accumulation in cells was observed by Oil-Red O staining and cells integrated optical density (IOD) value measured by Image-Pro Plus 6.0 analysis.…”

“…Reactive oxygen species (ROS) levels in the liver were measured using the fluorescent dye DHE (D7008, Sigma-Aldrich) as described previously (29). Briefly, the liver cryosections were incubated with fluorescent dye DHE for 30 min and the nuclei were labeled after treatment with 4',6-Diamidino-2-phenylindole dihydrochloride (DAPI) (D9542, Sigma-Aldrich) for 10 min.…”

“…In order to analyze the atherosclerotic lesions in the aorta, Oil-Red O staining was used to examine the 8 μm serial cross-sections of the aortic root and en face of the aorta, and Image-Pro Plus 6.0 software was used to quantify the lesions (29). Besides, the lipid deposition of macrophages and cryosections of the liver were also detected by Oil-Red O staining.…”

HDL Inhibited Atherosclerosis Induced by Radiation Injury

“…HDL is recognized to prevent or alleviate atherosclerosis through many pathways [12,13].whether the HDL can also promote the atherosclerosis caused by radiation and the mechanism is not clear. In this study, rstly we check the relationship between the ratio of atherosclerosis in radiation patients and the plasma lipid level; then we use MAECs treated by radiation to study the HDL role and possible mechanisms.…”