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

Inflamm Res. 2015 Apr;64(3-4):253-60. doi: 10.1007/s00011-015-0805-1. Epub 2015 Feb 27.


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.

MeSH terms

  • Angiotensin I / genetics
  • Angiotensin I / physiology*
  • Angiotensin II / physiology*
  • Angiotensin-Converting Enzyme 2
  • Animals
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Atherosclerosis / physiopathology
  • Atherosclerosis / prevention & control*
  • Cell Adhesion / physiology
  • Cell Movement / physiology
  • Chemokine CCL2 / physiology
  • Disease Models, Animal
  • E-Selectin / physiology
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / physiology*
  • Gene Transfer Techniques
  • Humans
  • In Vitro Techniques
  • Inflammation / physiopathology
  • Inflammation / prevention & control*
  • Mice
  • Peptide Fragments / genetics
  • Peptide Fragments / physiology*
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / physiology*
  • Signal Transduction / physiology*
  • Vascular Cell Adhesion Molecule-1 / physiology


  • Apolipoproteins E
  • CCL2 protein, human
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • E-Selectin
  • Peptide Fragments
  • Vascular Cell Adhesion Molecule-1
  • Angiotensin II
  • Angiotensin I
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2
  • angiotensin I (1-7)