Effects of the ACE2 inhibitor GL1001 on acute dextran sodium sulfate-induced colitis in mice

Inflamm Res. 2009 Nov;58(11):819-27. doi: 10.1007/s00011-009-0053-3. Epub 2009 Jun 11.

Abstract

Objective and design: Angiotensin-converting enzyme 2 (ACE2) is expressed in gastrointestinal tissue. Previous studies of GL1001, a potent and selective ACE2 inhibitor, have revealed anti-inflammatory activity in the mouse digestive tract. We hypothesized that GL1001 might also produce beneficial effects in a mouse DSS model of inflammatory bowel disease.

Materials: Female mice were used for study.

Treatment: Animals were treated for 5 days with 5% DSS in the drinking water to induce colitis. For the following 9 days, animals were treated twice daily with GL1001 (30, 100, 300 mg/kg, s.c.), sulfasalazine (150 mg/kg, p.o.), or vehicle.

Methods: Throughout the experiment, body weight, rectal prolapse, stool consistency, and fecal occult blood were monitored. At termination, colon length, histopathology, and myeloperoxidase activity were assessed.

Results: High-dose GL1001 ameliorated DSS-induced disease activity, including rectal prolapse and intestinal bleeding. The most robust effect of GL1001 was observed 48-96 h post DSS treatment and was comparable in magnitude to that of sulfasalazine. Colon pathology and myeloperoxidase activity were also markedly attenuated by high-dose GL1001 treatment, with the most profound effects observed in the distal segment.

Conclusions: The findings support the previously observed anti-inflammatory effects of ACE2 inhibition in gastrointestinal tissue and suggest that GL1001 may have therapeutic utility for inflammatory bowel disease.

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Animals
  • Body Weight / drug effects
  • Colitis / chemically induced*
  • Colitis / drug therapy*
  • Colitis / pathology
  • Colitis / physiopathology
  • Colon / enzymology
  • Colon / pathology
  • Dextran Sulfate / adverse effects*
  • Disease Models, Animal
  • Female
  • Humans
  • Imidazoles / therapeutic use*
  • Inflammatory Bowel Diseases / drug therapy
  • Inflammatory Bowel Diseases / pathology
  • Leucine / analogs & derivatives*
  • Leucine / therapeutic use
  • Mice
  • Mice, Inbred BALB C
  • Peptidyl-Dipeptidase A / metabolism
  • Peroxidase / metabolism
  • Random Allocation

Substances

  • 2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid
  • Angiotensin-Converting Enzyme Inhibitors
  • Imidazoles
  • Dextran Sulfate
  • Peroxidase
  • Peptidyl-Dipeptidase A
  • angiotensin converting enzyme 2
  • Leucine