PDF(Pubmed)
Abstract：
Human abdominal aortic aneurysms (AAAs) are characterized by increased activity of matrix metalloproteinases (MMP), including MMP-12, alongside macrophage accumulation and elastin degradation, in conjunction with superimposed atherosclerosis. Previous genetic ablation studies have proposed contradictory roles for MMP-12 in AAA development. In this study, we aimed to elucidate if pharmacological inhibition of MMP-12 activity with a phosphinic peptide inhibitor protects from AAA formation and progression in angiotensin (Ang) II-infused Apoe-/- mice. Complimentary studies were conducted in a human ex vivo model of early aneurysm development. Administration of an MMP-12 inhibitor (RXP470.1) protected hypercholesterolemia Apoe-/- mice from Ang II-induced AAA formation and rupture-related death, associated with diminished medial thinning and elastin fragmentation alongside increased collagen deposition. Proteomic analyses confirmed a beneficial effect of MMP-12 inhibition on extracellular matrix remodeling proteins combined with inflammatory pathways. Furthermore, RXP470.1 treatment of mice with pre-existing AAAs exerted beneficial effects as observed through suppressed aortic dilation and rupture, medial thinning, and elastin destruction. Our findings indicate that pharmacological inhibition of MMP-12 activity retards AAA progression and improves survival in mice providing proof-of-concept evidence to motivate translational work for MMP-12 inhibitor therapy in humans.
摘要：
人腹主动脉瘤（AAAs）的特征是基质金属蛋白酶（MMP）的活性增加，包括MMP-12，伴随着巨噬细胞积累和弹性蛋白降解，与叠加的动脉粥样硬化相结合。先前的基因消融研究提出了MMP-12在AAA发展中的相互矛盾的作用。在这项研究中,我们的目的是阐明,在血管紧张素(Ang)II型注射的Apoe-/-小鼠中,用一种次膦肽抑制剂对MMP-12活性的药理学抑制是否能保护AAA的形成和进展.在早期动脉瘤发展的人离体模型中进行了补充研究。施用MMP-12抑制剂（RXP470.1）保护高胆固醇血症Apoe-/-小鼠免于AngII诱导的AAA形成和破裂相关死亡，与减少的内侧变薄和弹性蛋白碎片以及增加的胶原蛋白沉积有关。蛋白质组学分析证实了MMP-12抑制对细胞外基质重塑蛋白与炎症途径组合的有益作用。此外，RXP470.1用预先存在的AAAs治疗小鼠，如通过抑制主动脉扩张和破裂观察到的，发挥了有益的作用。内侧变薄,和弹性蛋白破坏。我们的发现表明，MMP-12活性的药理学抑制延缓AAA进展并改善小鼠的存活率，提供了概念证据来激发人类MMP-12抑制剂治疗的翻译工作。
