Significance of Matrix Metalloproteinase-9 Inhibition by Imidapril for Prevention of Abdominal Aortic Aneurysms in Angiotensin II Type 1 Receptor–Knockout Mice

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.

Comparison of Efficacy between Ramipril and Carvedilol on Limiting the Expansion of Abdominal Aortic Aneurysm in Mouse Model

“…31 Attenuation of AAA progression by ACE inhibitors was demonstrated by decreasing the MMP-9 in AT1 receptor-knockout mice. 37 The pleiotropic and anti-inflammatory effects of ACE inhibitors may contribute to the antihypertensive effect inversely based on in vitro studies. 16,38,39 Ramipril as a representative ACE inhibitor exerts comprehensive anti-inflammatory effects on vessel wall inflammation in AAA disease by reducing mRNA expression of multiple proinflammatory cytokines and aortic specific wall proteins.…”

“…16 In addition, angiotensin receptor blocking agents may reduce free radicals which increase MMP and accelerate atherosclerotic plaque formation. 37…”

Significance of Vascular Dipeptidyl Peptidase-4 Inhibition on Vascular Protection in Zucker Diabetic Fatty Rats

“…The aorta was homogenized in 20 mM Tris-HCl buffer, pH 8.3, containing 5 mM Mg(CH 3 COO) 2 , 30 mM KCl, 250 mM sucrose, and 0.5% Nonidet P-40. The homogenate was centrifuged at 15,000 × g for 30 min, and the supernatant was used for measurements of DPP-4 activity and MDA levels (13).…”

In-Peptide Synthesis of Imidazolidin-2-one Scaffolds, Equippable with Proteinogenic or Taggable/Linkable Side Chains, General Promoters of Unusual Secondary Structures

“…In particular, the latter have been utilized as structural elements in peptidomimetic inhibitors of HIV protease and HIV replication, antibacterial MurB inhibitors, dopamine D4 and CGRP receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, serine protease inhibitors, and integrin inhibitors . In the literature, cyclic ureas are most commonly constructed via treatment of 1,2-diamine precursors with carbonyldiimidazole, or by intramolecular diamination of alkenes, via rearrangement of Asn, , via ring expansion of aziridine derivatives, by cyclization of aza-propargylglycinamides, by alkylation of the urea nitrogen of semicarbazone residues, by Pd-catalyzed urea carboamination reactions, and so on. Although a number of synthetic methods are available, many are not feasible in peptide chemistry.…”