title: Rosuvastatin activates ATP-binding cassette transporter A1-dependent efflux ex vivo and promotes reverse cholesterol transport in macrophage cells in mice fed a high-fat diet.
abstract: OBJECTIVE
  It is controversial whether statins improve high-density lipoprotein (HDL) function, which plays an important role in reverse cholesterol transport in vivo. The aim of the present study was to clarify the effects of rosuvastatin and atorvastatin on reverse cholesterol transport in macrophage cells in vivo and their underlying mechanisms.
  
  
  RESULTS
  Male C57BL mice were divided into 3 groups (rosuvastatin, atorvastatin, and control groups) and orally administered rosuvastatin, atorvastatin, or placebo for 6 weeks under feeding with a 0.5% cholesterol+10% coconut oil diet. After administration, although there were no changes in plasma HDL cholesterol levels among the groups, plasma from the rosuvastatin group showed an increased ability to promote ATP-binding cassette transporter A1-mediated cholesterol efflux ex vivo. In addition, capillary electrophoresis revealed a shift in HDL toward the pre-β HDL fraction only in the rosuvastatin group. Mice in all 3 groups were intraperitoneally injected with (3)H-cholesterol-labeled and cholesterol-loaded macrophages and then were monitored for the appearance of (3)H-tracer in plasma and feces. The amount of (3)H-tracer excreted into feces during 48 hours in the rosuvastatin group was greater than that in the control group. Finally, (3)H-cholesteryl oleate-HDL was intravenously injected into all groups, blood samples were taken, and the count of (3)H-cholesterol was analyzed. Plasma (3)H-cholesteryl oleate-HDL changed similarly, and no differences in fractional catabolic rates were observed.
  
  
  CONCLUSIONS
  Rosuvastatin enhanced the ATP-binding cassette transporter A1-dependent HDL efflux function of reverse cholesterol transport, and this finding highlights the potential of rosuvastatin for the regression of atherosclerosis.
authors.affiliation: From the Departments of Cardiology (T.S., S.M., H.T., T.K., Y.U., K.S.), Molecular Cardiovascular Therapeutics (S.M., Y.U., K.S.), Biochemistry (B.Z.), and Advanced Therapeutics for Cardiovascular Disease (H.T., K.S.), Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: From the Departments of Cardiology (T.S., S.M., H.T., T.K., Y.U., K.S.), Molecular Cardiovascular Therapeutics (S.M., Y.U., K.S.), Biochemistry (B.Z.), and Advanced Therapeutics for Cardiovascular Disease (H.T., K.S.), Fukuoka University School of Medicine, Fukuoka, Japan. miuras@cis.fukuoka-u.ac.jp.
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Miura
authors.affiliation: From the Departments of Cardiology (T.S., S.M., H.T., T.K., Y.U., K.S.), Molecular Cardiovascular Therapeutics (S.M., Y.U., K.S.), Biochemistry (B.Z.), and Advanced Therapeutics for Cardiovascular Disease (H.T., K.S.), Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanigawa
authors.affiliation: From the Departments of Cardiology (T.S., S.M., H.T., T.K., Y.U., K.S.), Molecular Cardiovascular Therapeutics (S.M., Y.U., K.S.), Biochemistry (B.Z.), and Advanced Therapeutics for Cardiovascular Disease (H.T., K.S.), Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuwano
authors.affiliation: From the Departments of Cardiology (T.S., S.M., H.T., T.K., Y.U., K.S.), Molecular Cardiovascular Therapeutics (S.M., Y.U., K.S.), Biochemistry (B.Z.), and Advanced Therapeutics for Cardiovascular Disease (H.T., K.S.), Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: From the Departments of Cardiology (T.S., S.M., H.T., T.K., Y.U., K.S.), Molecular Cardiovascular Therapeutics (S.M., Y.U., K.S.), Biochemistry (B.Z.), and Advanced Therapeutics for Cardiovascular Disease (H.T., K.S.), Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Uehara
authors.affiliation: From the Departments of Cardiology (T.S., S.M., H.T., T.K., Y.U., K.S.), Molecular Cardiovascular Therapeutics (S.M., Y.U., K.S.), Biochemistry (B.Z.), and Advanced Therapeutics for Cardiovascular Disease (H.T., K.S.), Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Keijiro
authors.initials: K
authors.lastname: Saku
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D000069059:Atorvastatin; D001692:Biological Transport; D002460:Cell Line; D002788:Cholesterol Esters / Q000097:blood; D002791:Cholesterol, Dietary / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D005260:Female; D005464:Fluorobenzenes / Q000494:pharmacology*; D006538:Heptanoic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D000069059:Atorvastatin; D002788:Cholesterol Esters; D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D015243:Cholesterol, VLDL; D005464:Fluorobenzenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides; C577833:Abca1 protein, mouse; C014409:cholesteryl oleate
keywords: ABC transporters; lipoproteins, HDL; macrophages; statins