title: MicroRNA 302a is a novel modulator of cholesterol homeostasis and atherosclerosis.
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.
  
  
  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.
authors.affiliation: From the Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu (S.M., Y.B., E.T., K.S., W.A.B.); Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (S.M.); and Kazan Federal University, Kazan, Russia (W.A.B.).
authors.forename: Svenja
authors.initials: S
authors.lastname: Meiler
authors.affiliation: From the Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu (S.M., Y.B., E.T., K.S., W.A.B.); Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (S.M.); and Kazan Federal University, Kazan, Russia (W.A.B.).
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Baumer
authors.affiliation: From the Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu (S.M., Y.B., E.T., K.S., W.A.B.); Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (S.M.); and Kazan Federal University, Kazan, Russia (W.A.B.).
authors.forename: Emma
authors.initials: E
authors.lastname: Toulmin
authors.affiliation: From the Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu (S.M., Y.B., E.T., K.S., W.A.B.); Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (S.M.); and Kazan Federal University, Kazan, Russia (W.A.B.).
authors.forename: Kosal
authors.initials: K
authors.lastname: Seng
authors.affiliation: From the Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu (S.M., Y.B., E.T., K.S., W.A.B.); Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (S.M.); and Kazan Federal University, Kazan, Russia (W.A.B.). wab@hawaii.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Boisvert
mesh_terms: D020413:3' Untranslated Regions; D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D016632:Apolipoprotein A-I / Q000097:blood; D050197:Atherosclerosis / Q000097:blood* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D019556:COS Cells; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000097:blood*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D058226:Plaque, Atherosclerotic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013997:Time Factors; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D002784:Cholesterol; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D011973:Receptors, LDL; C577836:ABCA1 protein, human; C577833:Abca1 protein, mouse; C558265:MIRN302 microRNA, mouse
keywords: ABCA1 protein; HDL cholesterol; atherosclerosis; cholesterol-efflux regulatory protein; macrophages; microRNA