ACE2 and Ang-(1–7) protect endothelial cell function and prevent early atherosclerosis by inhibiting inflammatory response

Background Angiotensin-converting enzyme 2 (ACE2) is a counter-regulator against ACE by converting angiotensin II (Ang-II) to Ang-(1–7), but the effect of ACE2 and Ang-(1–7) on endothelial cell function and atherosclerotic evolution is unknown. We hypothesized that ACE2 overexpression and Ang-(1–7)...

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Published in:Inflammation research 2015-04, Vol.64 (3-4), p.253-260
Main Authors: Zhang, Yue-Hui, Zhang, Yong-huan, Dong, Xue-Fei, Hao, Qing-Qing, Zhou, Xiao-Ming, Yu, Qing-Tao, Li, Shu-Ying, Chen, Xu, Tengbeh, Abdulai Fallah, Dong, Bo, Zhang, Yun
Format: Article
Language:English
Subjects:
Adenovirus
Allergology
Angiotensin I - genetics
Angiotensin I - physiology
Angiotensin II - physiology
Animals
Apolipoproteins E - deficiency
Apolipoproteins E - genetics
Atherosclerosis - physiopathology
Atherosclerosis - prevention & control
Biomedical and Life Sciences
Biomedicine
Cell Adhesion - physiology
Cell Movement - physiology
Chemokine CCL2 - physiology
Dermatology
Disease Models, Animal
E-Selectin - physiology
Endothelium, Vascular - cytology
Endothelium, Vascular - physiology
Gene Transfer Techniques
Humans
Immunology
In Vitro Techniques
Inflammation - physiopathology
Inflammation - prevention & control
Mice
Neurology
Original Research Paper
Peptide Fragments - genetics
Peptide Fragments - physiology
Peptidyl-Dipeptidase A - genetics
Peptidyl-Dipeptidase A - physiology
Pharmacology/Toxicology
Rheumatology
Signal Transduction - physiology
Vascular Cell Adhesion Molecule-1 - physiology
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Summary:Background Angiotensin-converting enzyme 2 (ACE2) is a counter-regulator against ACE by converting angiotensin II (Ang-II) to Ang-(1–7), but the effect of ACE2 and Ang-(1–7) on endothelial cell function and atherosclerotic evolution is unknown. We hypothesized that ACE2 overexpression and Ang-(1–7) may protect endothelial cell function by counterregulation of angiotensin II signaling and inhibition of inflammatory response. Methods We used a recombinant adenovirus vector to locally overexpress ACE2 gene (Ad-ACE2) in human endothelial cells in vitro and in apoE-deficient mice in vivo. The Ang II-induced MCP-1, VCAM-1 and E-selectin expression, endothelial cell migration and adhesion of human monocytic cells (U-937) to HUVECs by ACE2 gene transfer were evaluated in vitro. Accelerated atherosclerosis was studied in vivo, and atherosclerosis was induced in apoE-deficient mice which were divided randomly into four groups that received respectively a ACE2 gene transfer, Ad-ACE2, Ad-EGFP, Ad-ACE2 + A779, an Ang-(1–7) receptor antagonist, control group. After a gene transfer for 4 weeks, atherosclerotic pathology was evaluated. Results ACE2 gene transfer not only promoted HUVECs migration, inhibited adhesion of monocyte to HUVECs and decreased Ang II-induced MCP-1, VCAM-1 and E-selectin protein production in vitro, but also decreased the level of MCP-1, VCAM-1 and interleukin 6 and inhibit atherosclerotic plaque evolution in vivo. Further, administration of A779 increased the level of MCP-1, VCAM-1 and interleukin 6 in vivo and led to further advancements in atherosclerotic extent. Conclusions ACE2 and Ang-(1–7) significantly inhibit early atherosclerotic lesion formation via protection of endothelial function and inhibition of inflammatory response.
ISSN:1023-3830
1420-908X
DOI:10.1007/s00011-015-0805-1