Hypoxanthine induces cholesterol accumulation and incites atherosclerosis in apolipoprotein E©\deficient mice and cells
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J Cell Mol Med. 2016 Nov; 20(11): 2160¨C2172.
Published online 2016 Jul 11. doi: 10.1111/jcmm.12916
Hypoxanthine induces cholesterol accumulation and incites atherosclerosis in
apolipoprotein E©\deficient mice and cells
1Division of Nephrology and Department of Internal Medicine,
Kyungpook National University Hospital, Daegu, Korea
2BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science,
Kyungpook National University, Daegu, Korea
3Cell and Matrix Research Institute, Kyungpook National University, Daegu, Korea
Yong©\Lim Kim, Email: rk.ca.unk@mikly.
Abstract
Reactive oxygen species (ROS) generation during purine metabolism is associated
with xanthine oxidase and uric acid. However, the direct effect of hypoxanthine
on ROS generation and atherosclerosis has not been evaluated. Smoking and heavy
drinking are associated with elevated levels of hypoxanthine. In this study, we
investigated the role of hypoxanthine on cholesterol synthesis and
atherosclerosis development, particularly in apolipoprotein E (APOE)©\deficient
mice. The effect of hypoxanthine on the regulation of cholesterol synthesis and
atherosclerosis were evaluated in Apoe knockout (KO) mice and cultured HepG2
cells. Hypoxanthine markedly increased serum cholesterol levels and the
atherosclerotic plaque area in Apoe KO mice. In HepG2 cells, hypoxanthine
increased intracellular ROS production. Hypoxanthine increased cholesterol
accumulation and decreased APOE and ATP©\binding cassette transporter A1 (ABCA1)
mRNA and protein expression in HepG2 cells. Furthermore, H2O2 also increased
cholesterol accumulation and decreased APOE and ABCA1 expression. This effect
was partially reversible by treatment with the antioxidant N©\acetyl cysteine and
allopurinol. Hypoxanthine and APOE knockdown using APOE©\siRNA synergistically
induced cholesterol accumulation and reduced APOE and ABCA1 expression.
Hypoxanthine induces cholesterol accumulation in hepatic cells through
alterations in enzymes that control lipid transport and induces atherosclerosis
in APOE©\deficient cells and mice. These effects are partially mediated through
ROS produced in response to hypoxanthine.
Keywords: APOE, atherosclerosis, cholesterol, hypoxanthine, ROS
Introduction
Hypoxanthine, xanthine and uric acid are the products of the purine catabolism
pathway 1. The generation of reactive oxygen species (ROS) during purine
metabolism is well known 2. Xanthine oxidase and uric acid have been intensively
studied. However, the direct effect of hypoxanthine on ROS generation and
atherosclerosis has not been evaluated. Abnormal purine metabolism and purine
overproduction is related to Lesch¨CNyhan syndrome by purine salvage
enzyme¨Cguanine phosphoribosyltransferase (HGPRT) deficiency 3. Hypoxanthine acts
as a substrate for xanthine oxidase and is associated with ROS, which contribute
to vascular dysfunction and/or atherosclerosis 4, 5, 6. Cigarette smoking lowers
HGPRT activity and may increase the plasma hypoxanthine level 7. Alcohol
increases plasma concentrations of hypoxanthine 8. In addition, plasma
hypoxanthine levels increase in patients on haemodialysis, who present high
risks for cardiovascular diseases 9. Cigarette smoking, in addition to
increasing the risk of cardiovascular diseases, is known to increase total
cholesterol (TC), triglycerides (TG) and low©\density lipoprotein (LDL).
Alterations of the enzymes that control lipid transport may be a key underlying
mechanism 10. Although daily low to moderate alcohol intake is inversely related
to cardiovascular diseases, alcohol itself induces oxidative stress and
decreases apolipoprotein B levels. Heavy drinking may increase the risk of heart
disease, hypertension and stroke 11. Hypoxanthine could be associated with a
high risk of cardiovascular dysfunction and lipogenesis disorder in smoking or
heavy©\drinking populations and in patients on haemodialysis. However, there is
no direct evidence to support this association in the literature.
Hypoxanthine induces cholesterol accumulation and incites atherosclerosis in
apolipoprotein E©\deficient mice and cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082407/
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Br J Nutr. 2015 Aug 28;114(4):509-18. doi: 10.1017/S0007114515002159. Epub
2015 Jul 23.
Retinoic acid induces macrophage cholesterol efflux and
inhibits atherosclerotic plaque formation in apoE-deficient mice.
1
Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of
Public Health, Sun Yat-sen University (Northern Campus),Guangzhou,Guangdong
Province510080,People's Republic of China.
2
Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of
Stomatology, Sun Yat-sen University,Guangzhou,Guangdong Province510055,People's
Republic of China.
Abstract
It has been suggested that retinoic acid (RA) has a potential role in the
prevention of atherosclerotic CVD. In the present study, we used J774A.1 cell
lines and primary peritoneal macrophages to investigate the protective effects
of RA on foam cell formation and atherogenesis in apoE-deficient (apoE- / -)
mice. A total of twenty male apoE- / - mice (n 10 animals per group), aged 8
weeks, were fed on a high-fat diet (HFD) and treated with vehicle or 9-cis-RA
for 8 weeks. The atherosclerotic plaque area in the aortic sinus of mice in the
9-cis-RA group was 40¡¤7 % less than that of mice in the control group (P< 0¡¤01).
Mouse peritoneal macrophages from the 9-cis-RA group had higher protein
expression levels of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1)
than those from the control group. Serum total and LDL-cholesterol
Retinoic acid induces macrophage cholesterol efflux and inhibits
atherosclerotic plaque formation in apoE-deficient mice. - PubMed - NCBI
https://www.ncbi.nlm.nih.gov/pubmed/26201974
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