title: Angiotensin-(1-7) stimulates cholesterol efflux from angiotensin II-treated cholesterol-loaded THP-1 macrophages through the suppression of p38 and c-Jun N-terminal kinase signaling.
abstract: Angiotensin II (Ang II) and Ang-(1-7) are key effector peptides of the renin-angiotensin system. The present study aimed to investigate the effects of Ang-(1-7) on Ang II-stimulated cholesterol efflux and the associated molecular mechanisms. Differentiated THP-1 macrophages were treated with Ang II (1 µM) and/or Ang-(1-7) (10 and 100 nM) for 24 h and the cholesterol efflux and gene expression levels were assessed. Pharmacological inhibition of peroxisome proliferator-activated receptor (PPAR)γ and mitogen-activated protein kinases (MAPKs) were performed to identify the signaling pathways involved. The results demonstrated that Ang II significantly inhibited the cholesterol efflux from cholesterol-loaded THP-1 macrophages. Treatment with Ang-(1-7) led to a dose-dependent restoration of cholesterol efflux in the Ang II-treated cells. The co-treatment with Ang-(1-7) and Ang II significantly increased the expression levels of adenosine triphosphate (ATP)-binding cassette (ABC)A1 and ABCG1 compared with treatment with Ang II alone. This was coupled with increased expression levels of PPARγ and liver X receptor (LXR)α. The pharmacological inhibition of PPARγ significantly (P<0.05) eliminated the Ang-(1-7)-mediated induction of ABCA1 and ABCG1 mRNA expression. Treatment with Ang-(1-7) caused the inactivation of c-Jun N-terminal kinases (JNK) and p38 MAPK signaling in the Ang II-treated THP-1 macrophages. In addition, the inhibition of JNK or p38 MAPK signaling using specific pharmacological inhibitors mimicked the Ang-(1-7)-induced expression of PPARγ and LXRα. In conclusion, the data demonstrated that treatment with Ang-(1-7) promoted cholesterol efflux in Ang II-treated THP-1 macrophages, partly through inactivation of p38 and JNK signaling and by inducing the expression of PPARγ and LXRα. Ang (1-7) may, therefore, have therapeutic benefits for the treatment of atherosclerosis.
authors.affiliation: Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Yang
authors.affiliation: Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Bian
authors.affiliation: Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
authors.forename: Chuan-Shi
authors.initials: CS
authors.lastname: Xiao
authors.affiliation: Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Liang
authors.affiliation: Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
authors.forename: Nana
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
authors.forename: Fen
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Yang
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000096:biosynthesis; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000803:Angiotensin I / Q000008:administration & dosage; D000804:Angiotensin II / Q000008:administration & dosage; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D057093:Orphan Nuclear Receptors / Q000096:biosynthesis* / Q000235:genetics; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000008:administration & dosage; D012333:RNA, Messenger / Q000096:biosynthesis; D012084:Renin-Angiotensin System; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D010446:Peptide Fragments; D012333:RNA, Messenger; D000804:Angiotensin II; D000803:Angiotensin I; D002784:Cholesterol; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C118790:angiotensin I (1-7)