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

• Published in: Molecular medicine reports Vol. 12; no. 1; pp. 1387 - 1392
• Main Authors: YANG, HUI-YU, BIAN, YUN-FEI, XIAO, CHUAN-SHI, LIANG, BIN, ZHANG, NANA, GAO, FEN, YANG, ZHI-MING
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.07.2015; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: ABCA1 protein; Adenosine; Angiotensin; Angiotensin I - administration & dosage; Angiotensin II; Angiotensin II - administration & dosage; Apolipoproteins; Arteriosclerosis; Atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - genetics; Atherosclerosis - pathology; ATP; ATP Binding Cassette Transporter 1 - biosynthesis; ATP Binding Cassette Transporter, Sub-Family G, Member 1; ATP-Binding Cassette Transporters - biosynthesis; ATP-binding protein; c-Jun protein; Cholesterol; Cholesterol - metabolism; Gene expression; Gene Expression Regulation, Enzymologic; Genetic aspects; Humans; Immunoglobulins; JNK Mitogen-Activated Protein Kinases - biosynthesis; JNK Mitogen-Activated Protein Kinases - genetics; JNK protein; Kinases; lipid accumulation; Lipids; Liver X Receptors; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; MAP kinase; mitogen-activated protein kinase signaling; Mitogen-activated protein kinases; Molecular modelling; Orphan Nuclear Receptors - biosynthesis; Orphan Nuclear Receptors - genetics; p38 Mitogen-Activated Protein Kinases - biosynthesis; p38 Mitogen-Activated Protein Kinases - genetics; Peptide Fragments - administration & dosage; Peroxisome proliferator-activated receptors; Physiological aspects; Polymerase chain reaction; PPAR gamma - antagonists & inhibitors; Renin; Renin-Angiotensin System; Risk factors; RNA, Messenger - biosynthesis; Studies; Transcription factors; China; United States > US
• ISSN: 1791-2997; 1791-3004
• DOI: 10.3892/mmr.2015.3484

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.