Significance of matrix metalloproteinase-9 inhibition by imidapril for prevention of abdominal aortic aneurysms in angiotensin II type 1 receptor-knockout mice

J Pharmacol Sci. 2013;123(2):185-94. doi: 10.1254/jphs.13040fp. Epub 2013 Oct 4.

Abstract

To clarify the matrix metalloproteinase (MMP)-9 inhibitory effect of an angiotensin-converting enzyme (ACE) inhibitor in vivo, we evaluated the effect of an ACE inhibitor against elastase-induced abdominal aortic aneurysm (AAA) progression in mice. Molecular models showed that imidapril bound directly to the mouse MMP-9 active center. An active form of imidapril, imidaprilat, dose-dependently inhibited MMP-9 activity in the extract from elastase-induced AAA in wild-type mice. Imidapril (10 mg/kg per day) was administered to wild-type or angiotensin II type 1 (AT1) receptor knockout mice. Blood pressure was significantly lower in AT1 receptor-knockout mice than in wild-type mice, but imidapril did not affect blood pressure in AT1 receptor-knockout mice. The aortic diameter was significantly expanded after elastase application, but the expansion was significantly lower in AT1 receptor-knockout mice than in wild-type mice. In AT1 receptor-knockout mice, the aortic expansion was further attenuated by imidapril. MMP-9 activity in aorta was significantly augmented after elastase application. The MMP-9 activity was significantly lower in AT1 receptor-knockout mice than in wild-type mice, and it was further attenuated by imidapril. In conclusion, MMP-9 inhibition by imidapril might contribute to the attenuation of AAA progression in AT1 receptor-knockout mice.

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Animals
  • Aorta / diagnostic imaging
  • Aorta / enzymology
  • Aorta / pathology
  • Aortic Aneurysm, Abdominal / chemically induced
  • Aortic Aneurysm, Abdominal / genetics
  • Aortic Aneurysm, Abdominal / prevention & control*
  • Disease Models, Animal
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Gene Knockout Techniques
  • Imidazolidines / pharmacology*
  • Imidazolidines / therapeutic use*
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors / pharmacology*
  • Matrix Metalloproteinase Inhibitors / therapeutic use*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pancreatic Elastase / adverse effects
  • Receptor, Angiotensin, Type 1 / genetics*
  • Ultrasonography

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Imidazolidines
  • Matrix Metalloproteinase Inhibitors
  • Receptor, Angiotensin, Type 1
  • imidapril
  • Pancreatic Elastase
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse
  • imidaprilat