RESUMO
OBJECTIVE: Matrix metalloproteinase (MMP)-12 has been implicated in plaque progression and instability and is also amenable to selective inhibition. In this study, we investigated the influence of a greater than 10-fold selective synthetic MMP-12 inhibitor on plaque progression in the apolipoprotein E knockout mouse model of atherosclerosis. METHODS AND RESULTS: A phosphinic peptide (RXP470.1) that is a potent, selective murine MMP-12 inhibitor significantly reduced atherosclerotic plaque cross-sectional area by approximately 50% at 4 different vascular sites in male and female apolipoprotein E knockout mice fed a Western diet. Furthermore, RXP470.1 treatment resulted in less complex plaques with increased smooth muscle cell:macrophage ratio, less macrophage apoptosis, increased cap thickness, smaller necrotic cores, and decreased incidence of calcification. Additional in vitro and in vivo findings indicate that attenuated monocyte/macrophage invasion and reduced macrophage apoptosis probably underlie the beneficial effects observed on atherosclerotic plaque progression with MMP-12 inhibitor treatment. CONCLUSIONS: Our data demonstrate that a selective MMP-12 inhibitor retards atherosclerosis development and results in a more fibrous plaque phenotype in mice. Our study provides proof of principle to motivate translational work on MMP-12 inhibitor therapy in humans.
Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/prevenção & controle , Inibidores de Metaloproteinases de Matriz , Peptídeos/farmacologia , Inibidores de Proteases/farmacologia , Animais , Apolipoproteínas E/genética , Apoptose/efeitos dos fármacos , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Peso Corporal , Calcinose/enzimologia , Calcinose/prevenção & controle , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Fibrose , Bombas de Infusão Implantáveis , Infusões Subcutâneas , Lipídeos/sangue , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Macrófagos/patologia , Masculino , Metaloproteinase 12 da Matriz/deficiência , Metaloproteinase 12 da Matriz/genética , Camundongos , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Necrose , Peptídeos/administração & dosagem , Fenótipo , Inibidores de Proteases/administração & dosagem , CoelhosRESUMO
An unprecedented coupling of a P-C and a C-C bond-forming event in a practical operation was developed to access medicinally relevant phosphinic structures. The strategy relies on an Ireland-Claisen rearrangement triggered by the phospha-Michael addition of silyl phosphonites to allyl acrylates. This protocol was extended to a more versatile three-component variant that utilizes phosphinic acids, acryloyl chlorides, and allylic alcohols as starting materials.
Assuntos
Medicina , Ácidos Fosfínicos/química , Acrilatos/química , Carbono/química , Ácidos Fosfínicos/farmacologia , Fósforo/químicaRESUMO
Four phosphinic peptide libraries with compounds having the general formula p-Br-Ph-(PO2-CH2)-Xaa'-Yaa'-Zaa'-NH2 have been prepared and screened against 10 matrix metalloproteinases (MMPs). We identified two phosphinic peptides with Ki values of 0.19 and 4.4 nM toward MMP-12 (macrophage elastase) that are more than 2-3 orders of magnitude less potent toward the other MMPs tested. These highly selective MMP-12 inhibitors contain a Glu-Glu motif in their Yaa'-Zaa' positions. Incorporation of this Glu-Glu motif into the sequence of a nonspecific fluorogenic peptide cleaved by MMPs provides a highly selective substrate for MMP-12. A model of one of these inhibitors interacting with MMP-12 suggests that the selectivity observed might be due, in part, to the presence of two unique polar residues in MMP-12, Thr239 and Lys177. These MMP-12-selective inhibitors may have important therapeutic applications to diseases in which MMP-12 has been suggested to play a key role, such as in emphysema, atherosclerosis, and aortic abdominal aneurysm.