ACE2 activity was increased in atherosclerotic plaque by losartan: Possible relation to anti-atherosclerosis

J Renin Angiotensin Aldosterone Syst. 2015 Jun;16(2):292-300. doi: 10.1177/1470320314542829. Epub 2014 Jul 27.


Introduction: Angiotensin-converting enzyme 2 (ACE2) is a new member of the renin-angiotensin system (RAS) and it has been proposed that ACE2 is a potential therapeutic target for the control of cardiovascular disease. The effect of losartan on the ACE2 activity in atherosclerosis was studied.

Methods: Atherosclerosis was induced in New Zealand white rabbits by high-cholesterol diet for 3 months. An Angiotensin II (Ang II) receptor blocker (losartan, 25 mg/kg/d) was given for 3 months. ACE2 activity was measured by fluorescence assay and the extent of atherosclerosis was evaluated by H&E and Oil Red O staining. In addition, the effect of losartan on ACE2 activity in smooth muscle cells (SMCs) in vitro was also evaluated.

Results: Losartan increased ACE2 activity in atherosclerosis in vivo and SMCs in vitro. Losartan inhibited atherosclerotic evolution. Addition of losartan blocked Ang II-induced down-regulation of ACE2 activity, and blockade of extracellular signal-regulated kinase (ERK1/2) with PD98059 prevented Ang II-induced down-regulation of ACE2 activity.

Conclusions: The results showed that ACE2 activity was regulated in atherosclerotic plaque by losartan, which may play an important role in treatment of atherosclerosis. The mechanism involves Ang II-AT1R-mediated mitogen-activated protein kinases, MAPKs (MAPKs) signaling pathway.

Keywords: Ang-(1-7); Atherosclerotic plaque; angiotensin-converting enzyme 2; losartan; signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / metabolism
  • Angiotensin-Converting Enzyme 2
  • Animals
  • Down-Regulation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Losartan / pharmacology
  • Losartan / therapeutic use*
  • Male
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism
  • Peptide Fragments / metabolism
  • Peptidyl-Dipeptidase A / metabolism*
  • Plaque, Atherosclerotic / drug therapy*
  • Plaque, Atherosclerotic / enzymology*
  • Plaque, Atherosclerotic / pathology
  • Rabbits
  • Signal Transduction / drug effects


  • Peptide Fragments
  • Angiotensin I
  • Extracellular Signal-Regulated MAP Kinases
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • angiotensin I (1-7)
  • Losartan