Abstract
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.
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Acknowledgments
We would like to express our thanks to the teachers at the Key Laboratory of Cardiovascular Remodeling and Function Research, Shandong University. This study was supported by the National 973 Basic Research Program of China (No. 2013CB530700), the National Natural Science Foundation of China (No. 81170207) and the Program of State Chinese Medicine Administration Bureau (No. JDZX2012113).
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The authors report no conflicts of interest in this work.
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Responsible Editor: Ikuo Morita.
Yue-Hui Zhang, Yong-huan Zhang, and Xue-Fei Dong have contributed equally to the work.
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Zhang, YH., Zhang, Yh., Dong, XF. et al. ACE2 and Ang-(1–7) protect endothelial cell function and prevent early atherosclerosis by inhibiting inflammatory response. Inflamm. Res. 64, 253–260 (2015). https://doi.org/10.1007/s00011-015-0805-1
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DOI: https://doi.org/10.1007/s00011-015-0805-1