ABSTRACT
OBJECTIVE: Macrophage foam cell formation is a key feature of atherosclerosis. Recent studies have shown that specific microRNAs (miRs) are regulated in modified low-density lipoprotein-treated macrophages, which can affect the cellular cholesterol homeostasis. Undertaking a genome-wide screen of miRs regulated in primary macrophages by modified low-density lipoprotein, miR-302a emerged as a potential candidate that may play a key role in macrophage cholesterol homeostasis. APPROACH AND RESULTS: The objective of this study was to assess the involvement of miR-302a in macrophage lipid homeostasis and if it can influence circulating lipid levels and atherosclerotic development when it is inhibited in a murine atherosclerosis model. We found that transfection of primary macrophages with either miR-302a or anti-miR-302a regulated the expression of ATP-binding cassette (ABC) transporter ABCA1 mRNA and protein. Luciferase reporter assays showed that miR-302a repressed the 3' untranslated regions (UTR) activity of mouse Abca1 by 48% and human ABCA1 by 45%. In addition, transfection of murine macrophages with miR-302a attenuated cholesterol efflux to apolipoprotein A-1 (apoA-1) by 38%. Long-term in vivo administration of anti-miR-302a to mice with low-density lipoprotein receptor deficiency (Ldlr(-/-)) fed an atherogenic diet led to an increase in ABCA1 in the liver and aorta as well as an increase in circulating plasma high-density lipoprotein levels by 35% compared with that of control mice. The anti-miR-302a-treated mice also displayed reduced atherosclerotic plaque size by ≈25% and a more stable plaque morphology with reduced signs of inflammation. CONCLUSIONS: These studies identify miR-302a as a novel modulator of cholesterol efflux and a potential therapeutic target for suppressing atherosclerosis.
Subject(s)
Aorta/metabolism , Aortic Diseases/blood , Atherosclerosis/blood , Cholesterol/blood , Macrophages/metabolism , MicroRNAs/metabolism , 3' Untranslated Regions , ATP Binding Cassette Transporter 1/genetics , ATP Binding Cassette Transporter 1/metabolism , Animals , Aorta/pathology , Aortic Diseases/genetics , Aortic Diseases/pathology , Aortic Diseases/prevention & control , Apolipoprotein A-I/blood , Atherosclerosis/genetics , Atherosclerosis/pathology , Atherosclerosis/prevention & control , COS Cells , Chlorocebus aethiops , Diet, High-Fat , Disease Models, Animal , Homeostasis , Humans , Liver/metabolism , Mice, Inbred C57BL , Mice, Knockout , MicroRNAs/genetics , Oligonucleotides, Antisense/genetics , Oligonucleotides, Antisense/metabolism , Plaque, Atherosclerotic , Receptors, LDL/deficiency , Receptors, LDL/genetics , Time Factors , TransfectionABSTRACT
BACKGROUND: Our aim was to determine the incidence rates of head and neck cancer in Vietnamese Californians compared with other Asian and non-Asian Californians. METHODS: Age-adjusted incidence rates of head and neck cancer between 1988 and 2004 were computed for Vietnamese Californians compared with other racial/ethnic groups by time period, ethnicity, neighborhood-level socioeconomic status (SES), and sex using data from the population-based California Cancer Registry (CCR). Data by smoking and alcohol status were tabulated from the California Health Interview Survey. RESULTS: Vietnamese men had a higher incidence rate of head and neck cancer than other Asian men. Specifically, the laryngeal cancer rate was significantly higher for Vietnamese men (6.5/100,000; 95% confidence interval [CI], 5.0-8.2) than all other Asian men (range, 2.6-3.8/100,000), except Korean men (5.1/100,000; 95% CI, 3.9-6.4). Both Vietnamese and Korean men had the highest percentage of current smokers. Neighborhood SES was inversely related to head and neck cancer rates among Vietnamese men and women. CONCLUSION: The higher incidence rate of head and neck cancer in Vietnamese men may correspond to the higher smoking prevalence in this group. Individual-level data are needed to establish the link of tobacco, alcohol, and other risk factors with head and neck cancer in these patients.